Theories of Aging: From Damage and Programmed Theories to Goal-Directedness

1. Introduction

Aging is an extensive biological process characterized by morphological and functional alterations at different biological levels, resulting in a systematic decline in biological functions ultimately leading to death [1,2,3]. Genetic inheritance, environmental conditions, and lifestyle can influence the aging process [4]. Several diseases are related to aging, as the resistance to noise and damage decreases, including cardiovascular diseases, cancer, neurogenerative conditions, diabetes, and immune-related diseases with inflammation, altering significantly the quality of life [5,6] and limiting our potential for growth that may require more than the evolutionarily standard human life span [7].

The current aging literature provides a good understanding of the currently-detectable hallmarks of aging [6]; however, which are consequences and which are drivers of the aging process is still unclear [8]. Moreover, researchers are not really in agreement on a definition of aging [9] or its ultimate cause. Overall, two main types of theories have been proposed: damage accumulation-based theories [5,6,10] and evolutionary programmatic theories [1,11,12]. Over the past century, aging theories have consistently highlighted whichever biological subsystem gained scientific prominence during that particular period. This pattern has resulted in distinct theoretical frameworks that emphasize individual components—whether genetic elements like telomeres, mechanisms controlling gene expression, immune system components, reactive oxygen molecules, or epigenetics to name a few [13]. Most of the major theories are supported by good scientific evidence in the literature; however, they tend to focus on a particular sub-component of the general physiology, illustrating that it is key for the healthy functioning of the biological system and that its dysfunction can lead to aging. But there is still no unified approach explaining why all the critical components of the biological system at different scales degrade with time after development.

Here, we attempt a conceptual mindmap of this diverse and important field. We also propose a third option, framed in the perspective of biological systems composed of nested layers of competent subsystems with agendas [14,15,16,17]: aging as loss of goal-directedness. On this model, aging is first and foremost a failure mode unique to aligned collectives with goal-directed behavioral capabilities at multiple scales. One such collective is groups of cells during morphogenesis, whose activities are functionally held together by a large-scale goal state (the species-specific target morphology), which the group pursues in the space of anatomical possibilities [16,18]. What does such a system do, long after the body is constructed? We propose that after the developmental phase has been completed, cells begin to lose collective alignment. On this view, aging, like cancer [19,20], is a failure of the fundamental driver of multicellularity (shared homeostatic setpoints). The ultimate driver of aging is thus fundamentally a problem that belongs to cybernetics or cognitive science [13,21], not physics (as in damage theories) nor evolutionary biology (as in programmatic theories). It predicts that aging phenomena will occur even in the absence of accumulated damage or evolutionary forces [22]. We add therefore a third theoretical aging category grounded in biological systems seen as collective intelligence [22,23,24].

Here, we attempt to synthesize a simplified conceptual map of the field to emphasize distinct proposed drivers and their numerous sequalae, and discuss implications of the various theories for biomedical approaches to longevity.

2. Theories of Aging

Damage-Based Theories

Damage-based theories propose that aging arises from the accumulation of entropic damage, which affect essential molecular and cellular components such as the genome, telomeres, mitochondria, and proteins. This process would be caused by the inherent imperfections in cellular repair mechanisms [5,6,10]. On this view, aging is the result of inescapable rising disorder – in other words, its origin lies in physics, not biology. This family of theories comprises several different versions, focusing on different aspects of aging and on different levels of biological complexity:

• Molecule level:

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  DNA damage theory/mutation accumulation theory: aging occurs because of accumulation of germline mutations that are neutral during development and early reproductive life, and thus do not get the benefit of repair efforts, but then are deleterious in the late life [25,26].

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  Telomere theory: the aging process is driven by the progressive accumulation of mutations that limit cellular division capacity, mainly due to the gradual shortening of telomeres during each cycle of cell division [27].

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  Protein damage theory/Error catastrophe theory: it suggests that that aging results from the accumulation of errors in protein synthesis, leading to a cascade of cellular dysfunction and the eventual failure of cellular systems. This theory posits that once error levels exceed a critical threshold, they trigger a rapid and irreversible decline in cellular function, causing aging [28].

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  Mitochondrial theory of aging: it is an extension of the free radical theory of aging and suggests that as mitochondria are involved in regulating programmed cell death, but their functions are especially vulnerable to damage from free radicals, this sensitivity leads to genetic mutations, which in turn increase free-radical production, perpetuating a self-amplifying cycle of cellular damage [29].

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  Free radical theory: it posits that molecular damage results from the metabolic reactivity of partially reduced molecular oxygen (ROS). These ROS cause oxidative damage to lipids, proteins, and DNA [30].

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  The deleteriome theory of aging: it suggests that endogenous damage is a by-product of imperfect metabolic processes and results from most if not all biological functions [3] at all levels, from molecular, cells, organs, and systems. This leads to damage accumulation and ultimately aging.

• Cell-level:

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  Stem cell theory: aging is due to the depletion and/or dysfunction of stem cells with age.

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  Cellular senescence theory: aging is caused by non-dividing senescent cells that accumulate with age.

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  Immune system theory: it posits that aging is due to immune system dysfunction and higher inflammation with age [31].

• Informational layers:

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  Loss of bioelectrical morphostatic information: aging is caused by the alteration of the bioelectric pattern in charge of the maintenance of the anatomy or the inability of the cells to understand and integrates the bioelectrical pattern [23].

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  The information loss theory/epigenetics theory: these theories posit that aging is caused by DNA damage-driven loss of epigenetic information [32] producing a loss of cell identity leading to aging [33].

Most anti-aging treatments that have been developed so far revolve around the damage-based theories with a particular emphasis on epigenetic interventions with Yamanaka factors and derivatives [34] (see Table 1).

(Quasi) Programmatic-Based Theories

In contrast to physics-focused theories that emphasize inevitable wear-and-tear damage at different levels, programmatic theories suggest that aging is genetically or evolutionarily predetermined, placing evolutionary forces as the ultimate cause of aging [11,35,36]. Quasi-programmed theories focus on development, aging is here an unintended consequence of developmental and growth programs running in later life; selection is weak against these harmful late effects. These theories hold that aging is not inevitable, but specific aspects of evolution have favor it (or favored development). Under this category, we can find:

• Evolutionary trade-off ones:

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  Disposable soma theory: it posits that organisms allocate limited resources between reproduction and maintenance of the body (soma). Since resources are finite, investing heavily in reproduction reduces the resources available for cellular repair [37]. Here, aging is a product of an evolutionary trade-off.

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  Antagonistic pleiotropy theory: important wild-type genes that govern growth and development accelerate aging later in life [2,38].

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  Hyperfunction theory: aging is a result of normal growth and developmental pathways that continue excessively or inappropriately beyond their intended period, causing harmful activity (hyper- or hypofunction) in cells and tissues [39].

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  Software design flaw theory: it posits that aging results from pre-existing flaws or limitations in the organism’s genetic program—akin to a “bug” or imperfect design in the biological “software”—which becomes apparent as the organism ages [11]. Another possibility is evolutionary commitment to specific mechanisms which cause aging as a side-effect but cannot be improved by evolutionary search due to important dependencies.

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  Group selected adaptation: aging evolved to control or limit the death rate over time helping stabilize population dynamics to respect ecological limits and prevent extinctions [40].

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  The adaptation/maladaption theory: it proposes that in aging adaptation processes such as adaptive transcription, epigenetic remodeling, and metabolic plasticity drive dysfunction themselves over time (maladaptation) and thereby cause aging-related disorders [41].

Figure 1. The theoretical landscape of aging. Tree of aging theories by categories from ultimate causes to biomedical interventions. They are classified in 3 larger categories: damage-based, programmatic and collective intelligence-based theories.

Figure 1. The theoretical landscape of aging. Tree of aging theories by categories from ultimate causes to biomedical interventions. They are classified in 3 larger categories: damage-based, programmatic and collective intelligence-based theories.

Specific systems evolution targeted:

• Neuro-endocrine theory: aging is due to the modulation of cell cycle signaling by reproductive hormones [42].
• Pathogen-control theory: aging evolved to control or limit the spread and impact of pathogens within a species. The mechanism has been proposed to be the immune system [43,44,45,46] but in general is compatible with other means of removing old (and thus presumed infected) individuals from the population.

Goal-Directedness-Based Theory

“Cancer is no more a disease of cells than a traffic jam is a disease of cars. A lifetime of study of the internal-combustion engine would not help anyone understand our traffic problems.” -- D. W. Smithers

Whereas the above theories place the ultimate cause of aging in physics and evolutionary biology respectively, we propose a set of hypotheses which propose aging to be fundamentally a problem of cybernetics (or cognitive science): a misalignment of components within a goal-seeking system once its goals have been met. In other words, nothing needs to be wrong at the hardware level, in the same sense that psychological disorders can arise without organic disease. Imagine a scenario in which a human, a dog, and a snake are put into an ideal environment devoid of any source of infection or molecular damage (a kind of perfect afterlife perhaps, with no entropy), and in which all somatic aging processes are halted. While we don’t know what would happen, one could imagine that the snake would be fine forever, and perhaps the dog would as well – happily chasing rabbits and sleeping in the sunny grass for trillions of years. But, does it seem likely that a human mind could remain sane for enormous lengths of time? If not, it would have to be caused by a psychological dynamic – a failure mode that isn’t due to molecular entropic forces or tissue degradation but is uniquely characteristic of advanced cybernetic systems that become unstable after the have achieved their primary goal but do not have new ones to pursue.

It is tempting to hypothesize that homeodynamic systems operating in other spaces (not just the familiar brain-based cognition driving behavior in 3D space [47]) may be susceptible to this problem as well. Morphogenesis is precisely such a system, as many of its instances implement a goal-seeking pattern homeostasis process that minimizes error relative to a setpoint (an anatomical state) via growth, remodeling, apoptosis, and other effector processes in embryogenesis and regeneration [47]. Such setpoints can be stored (as in the brain) in tissue-level bioelectric patterns [16] but many kinds of biomechanical or biochemical encodings exist as well. In this sense, the departure from coherent functional anatomy in cancer is also a disorder of collective alignment: cells disconnecting from information networks that allow the group to pursue large (organ-level) setpoints [48,49,50], and reverting to ancient tiny goals focused on metabolic and physiological states at their small scale. Such disconnection and its downstream consequences can be caused by molecular (genetic or otherwise) damage, but also by physiological stressors and other dynamics [51,52,53,54,55,56]. We suggest there are important parallels at the intersection of aging, cancer, and cognitive science broadly conceived [57].

Goal-directedness [58] (used here in the minimal, cybernetic sense of error minimization, not in the full-blown metacognitive sense of an intelligent agent knowing their goals [59,60,61,62]) refers to the fact that in multiscale biological systems, higher levels of organization work to achieve homeostatic, homeodynamic, and allostatic setpoints in spaces that are inaccessible to their parts. For example, while individual cells manage goals [59,60,61,62]in metabolic and physiological state space, groups of cells work towards implementing and maintaining complex 3-dimensional states in anatomical morphospace [63,64,65]. Regeneration and maintenance of anatomical form by morphogenetic processes is a closed-loop process that implements error-reduction with respect to a stored goal state. This requires alignment of components, which can break down, as occurs in the case of cancer [19,20]. While such a breakdown of cooperativity can have many causes (including the ones discussed above), multiscale architectures can generate unique disease conditions that are not due to problems with any of their parts. Traffic jams are a good example of unique dynamics arising at higher levels of organization [66,67,68,69,70]. We propose that one such unique disease state can occur in goal-seeking systems that have completed their goal, and in the absence of a new motivating driver, begin to disband (i.e., no longer prevent their semi-autonomous parts – cells – from becoming misaligned) [23]. Specifically, we propose that aging can be caused by cellular collectives having completed their journey in anatomical space and having no new setpoint to implement. Under this general framework, we can place:

• Loss of goal-directedness theory: aging is caused by the loss of goal-directedness after the primary morphogenetic setpoints are achieved during development. This leads to a failure of alignment of cell behavior toward large-scale anatomical setpoint patterns, and thus degradation of order at all scales [22,57,71,72].
• Imperfect memory theory: cells lose the memory of resilient behavior under stress leading to general dysfunction [13]. We add that relevant memories may be of molecular states, physiological states, transcriptional states, or even second-order memories of policies (resilient ways to deal with inputs), not just static setpoint patterns.

The imperfect memory [13] and loss of goal-directedness are very close, while both are part of the collective intelligence category view on biological systems emphasize two different aspects of aging. The imperfect memory theory states that aging and death result from the accumulation of imperfect cellular memories of appropriate behavior under stress due to the inherent ambiguity of biological information [13]. Over time, these imperfect memories accumulate and overwhelm the flexibility cells require to respond adaptively to environmental stresses, leading to a gradual breakdown in cellular information assessment and cell-cell communication. This approach is very similar to the loss of morphostatic information one as bioelectrical patterns can be interpreted as anatomical memories [16,73]. The loss of goal-directedness one suggests that this is the absence of anatomical goal that produces multiscale breakdown and aging. While both frameworks use the cognitive lens on biological systems and frame aging as a defect of information processing, they differ in the cognitive and scale implementations. The former focus on the accumulation of imperfect cellular memories (which is also close to the accumulation of damage reframed in an information-theoretic lens), the latter focus on the lack of anatomical goal, the absence of maintenance/regenerative instructions, causing aging even in the absence of accumulated damage in a multi-competency architecture.

3. Anti-Aging Interventions

The current scientific landscape of anti-aging interventions targets mostly the hallmarks of aging [6] and integrates very different biomedical interventions including chemical-based, epigenetic, blood-based, senolytics and lifestyle approaches (see Table 1). While sustained caloric restriction and mTOR inhibitors like rapamycin remain the best-evidenced interventions for modulating aging biology in existing human data [74,75], the field is increasingly pivoting toward more transformative modalities. Partial epigenetic reprogramming has emerged as the most funded approach, driven by multibillion-dollar investments in ventures like Altos Labs, with recent data demonstrating its ability to safely reset epigenetic clocks and improve tissue function in non-human primates and mice without stripping cell identity [76]. However, despite this potential, clinical translation is severely constrained by fundamental safety and efficacy hurdles. Partial reprogramming strategies are constrained by toxicity: continuous or high-level expression of OSKM factors drives rapid dedifferentiation and loss of cellular identity, causing teratomas [77]. This has been overcome in several models by using transient, low-dose OSKM factors which preserves identity and avoids teratomas while enabling rejuvenation [78,79]. However, systemic induction of OSKM factors has been shown to precipitate acute hepatic and intestinal failure, leading to premature death [80]. Myc-sparing expression (OSK) has also been used in vivo: in mouse retinal ganglion cells, OSK restored youthful DNA-methylation and transcriptional profiles, promoted axon regeneration, and improved visual function [81].

Concurrently, exosome-based interventions are developing as a cell-free alternative to paracrine rejuvenation; extracellular vesicles derived from young plasma or mesenchymal stem cells have demonstrated the capacity to transfer bioactive miRNAs that suppress the senescence-associated secretory phenotype (SASP) and restore mitochondrial homeostasis in aged tissues [82,83].

One important question in the context of anti-aging interventions that needs to be answered is to determine if (and what) combination(s) (number and category) of established intervention(s) act synergistically for cumulative benefit that will impart the desired health and or lifespan enhancements. For example, combining Yamanaka factors + Senolytics produced synergistic effects in flies in terms of substantially longer mean and maximum lifespan, while each treatment alone had limited benefits- OKSM alone offered maximum lifespan (rejuvenated stem cells), while Sen expression alone (removed senescent cells) increased mean lifespan but had no effect on maximum lifespan. Another study in flies with different genetic backgrounds [84], reported on achieving exceptional lifespan extension in flies (D. melanogaster) using multitude of potential anti- aging approaches such as dietary restriction, co-administration of berberine, fucoxanthin, and rapamycin, photo-deprivation, and low-temperature conditions. The strongest effect was observed when all of the mentioned factors were combined, producing a 122% increase in median lifespan and a 124% increase in maximum lifespan in long-lived mutant E(z)/w males. Authors noted that some of the factors investigated when used singly and in combination, impacted the lifespan negatively, while some did not offer any advantage over the control group (effects were sex dependent as well). The study concluded that even if some of the factors did not impart any significant effect when tested alone, their combined action seemed to offer lifespan enhancements, indicating these interventions probably acted synergistically. The geroprotective effects of these interventions were shown to affect the evolutionarily conserved longevity molecular pathways, mTOR signaling modulation, significant increase in foxo and Akt1 gene expression, decrease in Hsp70 gene expression and autophagic mechanisms.

Transient expression of OSKM was shown to be beneficial in flies, while long term or sustained expression was detrimental [85]. The OSKM factors are believed to work by reversing the loss of epigenetic information (an “information theory of aging”) and rejuvenating mitochondrial function. Related to enhanced mitochondrial function as an anti-aging approach is the approach of initiating ‘mitophagy’ (autophagy of mitochondria specifically) by exercise, natural compounds such as Urolithin A and EGCG and/or supplements containing these compounds, with Rapamycin also showing beneficial effect. It will be interesting to test the combination of these factors for their cumulative or synergistic effects as noted above for other such interventions.

One major limitation in the studies we have reviewed here is that the reported human data is largely of healthspan increase rather than lifespan longevity, studies of which are available in other model systems. However, as the research progresses faster and the attention along with the funding this field is getting, we will begin to see real human data in near future. A few encouraging results have been reported, particularly for Rapamycin. These include PEARL trial (NCT04488601) that established safety and tolerance of low dose Rapamycin in healthy aged cohort (50-85 years), resulting in significantly increased lean tissue mass and bone density, pain reduction and improved overall emotional and physical health [86]. Other studies are investigating effect of low dose Rapamycin on enhancing ovarian function and IVF success (VIBRANT trial, NCT05836025), another study demonstrated increased in vitro fertilization (IVF) rates after repeatedly failed cycles, better quality blastocysts resulting in more successful live births [87].

However, demonstrating actual rejuvenation at organismal level in mammals has not been achieved yet. But we can mention that very recently, it has been reported in a preprint that by rejuvenating CD4+ T-cells and reinjecting them in mice could extend lifespan with a 65% increase creating ‘rivers of telomerase’ (Treatment Median 43–45 months vs. Control Median 26–28 months) [88]. Some mice reached twice the normal lifespan of a mice (~60 months) which is a huge gain. Indeed, the gold standard with rapamycin or caloric restriction typically delivers typically delivers a 15–25% median extension [89,90]. If true and this result can be translated to humans, this would be the first intervention that can really delay aging past the current known limits of human lifespan.

4. Unconventional Aging Mechanisms: Bioelectric Patterns and Phylogenetic Drift

Two new recent mechanisms have been proposed to function during the process of aging. The first is progressive degradation of bioelectrical pattern information, and the loss of alignment of cellular transcriptomes with respect to phylogenetic age. Both of these are most clearly connected to the memory loss theories, and in general the goal-directedness root cause model, because those focus on information and the biophysical encodings of homeostatic goal states. But, both are compatible with damage and programmatic causes as well, as they can be due to numerous upstream events.

The Bioelectrical Pattern as the Encoded Morphogenetic Goal

Developmental bioelectricity is increasingly recognized as a global coordinator of growth and form and the encoding of anatomical setpoints [91,92,93,94]. Indeed, through the voltage dynamics governed by ion channels and pumps, cells execute complex computational operations that regulate their behavior [73]. Evolution recognized early—dating back to the emergence of bacterial biofilms [95,96,97] — that bioelectric networks provide an efficient medium for integrating information across spatial and temporal scales, enabling coordinated activity among individual cellular units towards higher large-scale tasks. This principle underlies the organization of both nervous systems and artificial computers, which similarly exploit electrical signaling for large-scale information processing tasks, probably the same reason brains and computers exploit it [98].

Bioelectric signaling dynamics govern a wide range of developmental and regenerative processes, including wound repair, neural circuit formation, organogenesis, and body axis specification [99]. Recent work has demonstrated that modulation of bioelectrical patterns offers a high-level control interface for morphogenesis and regenerative medicine [73,99,100]. Instead of micromanaging molecular events, bioengineers can exploit simple electrical cues to trigger complex, self-limiting cascades of tissue development. Practical strategies span from guiding cell migration through electrotaxis during healing [101,102] to manipulating ion channels with “morphoceuticals” compounds that set bioelectric prepatterns for appendage or organ induction [100]. For example, in vertebrates, craniofacial morphogenesis is guided by distinct bioelectric gradients that spatially organize gene expression, thereby defining the positions of the eyes, mouth, and other facial structures [94,103,104,105]. Experimental alteration of these electrical patterns through targeted ion channel misexpression, as well as genetic channelopathies (reviewed in [106]), can reproduce morphogenetic programs in non-native regions, inducing the formation of complete ectopic organs—such as eyes developing on the gut of tadpoles [107]. These findings reveal that bioelectric cues can unlock latent developmental programs within tissues that are normally non-competent for this specific organogenesis, such as inducing new growth of whole multi-tissue appendages [108,109,110,111,112,113].

The stopping of the maintenance of the bioelectrical pattern and the associated loss of bioelectrical morphostatic information is a possible mechanistic substrate for the loss of goal-directedness at the tissue and organ levels. Voltage gradients and ion channel networks encode and maintain anatomical setpoints—the information that tells cells and tissues what to grow. The decay of these bioelectric patterns with age leads to a loss of anatomical homeostasis, causing tissues to drift structurally and functionally. These bioelectric circuits, a crucial part of the “physiological software of life” [23], serve as an informational layer that enables large-scale anatomical patterning, working synergistically with genetic hardware. When the precision of these bioelectric patterns degrades or cells lose their ability to sense them, tissues drift away from optimal morphologies, leading to organ dysfunction, disease, and death. Bioelectric signals provide real-time feedback and coordination between cells, tissues, and organs. This layer can encode critical processes such as regeneration, developmental patterning, and cancer suppression [16,20,23,73,99]. When the maintenance of these bioelectric prepatterns is stopped, leading their corruption over time, it is hypothesized that it drives anatomical and functional aging, with channelopathies emerging as a unifying mechanism for many age-related diseases [23,114,115].

Bioelectricity interfaces with established molecular hallmarks of aging. Evidence and plausible mechanistic links are described between ion channel dysfunction and age-dependent degenerative phenomena—including for example senescence, stem cell exhaustion, inflammation (“inflammaging”), loss of proteostasis, and altered nutrient sensing [23,116].. Notably, the bioelectric layer both influences and is influenced by other molecular processes, suggesting reciprocal causality and bidirectional feedback within aging phenotypes [23,116]. In exploring the consequences of the impairment of coordinating and setpoint-encoding information, we reasoned that detectable loss of alignment would be observed among downstream molecular properties regulated by large-scale information systems.

Transcriptional Level Loss of Morphogenetic Control: The Atavistic Genetic Expression Dissociation (AGED)

In searching for signs of misalignment across cells as a function of aging, normally observed at the spatial level, we sought to examine the temporal dimension, and in particular include scales well beyond the single organism lifespan. We thus found a transcriptional atavistic dissociation that operates at the genomic and cellular level during aging [24]: a progressive increase in the disagreement among cells of their evolutionary age. The “Atavistic Genetic Expression Dissociation (AGED)” data reveal that aging is not merely a uniform reversion to ancient gene expression like in cancer [117,118], but fundamentally a process of dissociation and loss of multicellular coordination across tissues and transcriptional programs at the evolutionary scale. This dissociation manifests as a heterogeneous, tissue-specific shift and dispersion of gene expression profiles: instead of all tissues reverting to the same ancestry, each tissue can regress along different evolutionary trajectories [24]. This has been found for two multi-tissue aging databases covering skin, ovarian, immune, senescent and mesenchymal-senescent cells, but interestingly not for brain cells and mesenchymal stem cells. It suggests that cells are lost in phylogenetic space, and tissues lose a unified transcriptional identity and regress in divergent ways. This is related to the loss of identity we can find too during aging [33,119]. When crucial information, especially patterns that serve as instructive anatomical setpoints, degrade within the multi-scale competency architecture of a metazoan body, the normal coordination of morphogenesis can slide backwards, allowing the cells to follow their own goals in their problem space, leading to the atavistic dissociation [24] and/or cancer [63].

Figure 2. Multiscale breakdown of morphogenetic control of form. The loss of goal-directedness theory is the most general one. When the cells have an anatomical goal, they are aligned and behave towards that goal creating a larger cognitive light cone. When cells lack the higher goal, they are misaligned, desynchronize and follow their own cellular goals. By going down in scale, we can find two possible mechanistic implementations: the loss of bioelectrical morphostatic information and downstream at genetic level, the atavistic genetic expression dissociation (cancer is another possible cellular goal) where cells are lost in phylogenetic space.

Figure 2. Multiscale breakdown of morphogenetic control of form. The loss of goal-directedness theory is the most general one. When the cells have an anatomical goal, they are aligned and behave towards that goal creating a larger cognitive light cone. When cells lack the higher goal, they are misaligned, desynchronize and follow their own cellular goals. By going down in scale, we can find two possible mechanistic implementations: the loss of bioelectrical morphostatic information and downstream at genetic level, the atavistic genetic expression dissociation (cancer is another possible cellular goal) where cells are lost in phylogenetic space.

5. Future Roadmap for Therapeutics

Organisms such as planaria, or hydra, as well as the continued youthfulness of our germline, serve as existence proofs demonstrating that practically infinite maintenance and amortality are possible. There are life forms that resolve the aging problem at the systems level. It is important to complement existing focus [120,121] on molecular- and cell-level therapeutics with novel approaches that target emerging information-level factors in health and disease [122,123,124,125,126,127,128,129].

Our framework has several implications for roadmaps to longevity. First, robust mechanisms for maintaining and implementing morphogenetic setpoint states (i.e., a robust regenerative response) should be associated with minimal aging and cancer. With respect to cancer, it has long been known that high regenerative capacity (the ability to re-implement anatomical structure with high fidelity) prevents the breakdown into autonomous, lower-level cellular goals like tumorigenesis [20] – well-documented among species with continuous, highly controlled growth and rare cancer incidence [130,131,132,133,134,135,136]. Moreover, evidence from diverse taxa illustrates that some species—such as lobsters, planaria, Greenland sharks, long-lived trees, and fungi—demonstrate negligible senescence while demonstrating sustained regenerative or growth capacities throughout their lifespans [130,137,138,139,140,141]. Thus, we propose that the fundamental way to address aging is the same as that for birth defects, traumatic injury, and cancer: as fundamentally disorders of collectivity, all of these maladies will be addressed by definitive progress in regenerative medicine targeting native morphogenetic programs [142,143,144]. Asexual planaria may be immortal precisely because they can avoid the loss of goal-directedness: every two weeks, they motivate their anatomical homeostatic systems by fissioning: each fragment must re-scale (and thus re-write, sharpen, and renew) the bioelectric and biochemical setpoints, and commit to implementing the goal state. Planaria are never bored of their embodiment, and this confers immortality despite their extremely noisy genome [145,146]. It is not yet known how much or how little repair is needed to refresh the morphogenetic system – does longevity require massive regenerative response as in planaria? Would extremely long lifespans require actual modification of anatomy (a caterpillar-butterfly kind of event, currently entertained on the domain of future-looking transhumanism)? The benefits of exercise (small-scale microtrauma [147]), and the immortality in Hydra (budding, not whole-animal regeneration) provide reason to be optimistic [20,130,148].

A roadmap is emerging. By focusing on reimposing large-scale (whole anatomy) morphogenetic goal, it may be possible to engineer organismal rejuvenation. The regenerative experiment in [22] suggests that giving an embryonic environment to the cells after the loss of one organ during aging may re-active developmental/regenerative pathways, much as embryonic environments have been shown to normalize cancer [149,150,151,152,153]. This is similar to regeneration observations with Yamanaka factors during partial cell reprogramming [154]. Likewise, new ways to detect disorganization at the system level (e.g., the atavistic phylostratigraphy signature discussed above), and non-invasive detection of bioelectric pattern anomalies, as for cancer [155], suggest novel monitoring modalities complementing epigenetic and transcriptional clocks [156,157].

The bioelectric theory in particular suggests an interesting intervention path to longevity: refreshing the bioelectric patterns. A proof of concept of this already exists, in the field of birth defects in the Xenopus model. A number of teratogenic interventions exert their effects by degrading the native bioelectric patterns that establish the correct structure of the brain, face, heart, and gut. Remarkably, whether induced chemically or genetically (Notch mutation), these defects can be over-ridden by a single ion channel activation (via pharmacological or mRNA-induced means), resulting in a sharpening of the bioelectric prepatterns and the return of the anatomical, gene expression, and behavioral endpoints to wild-type despite the continued presence of the teratogenic agent [110,111,158]. Thus, in at least some cases, hardware defects can be repaired “in software” via physiological stimuli induced by a computational platform-selected electroceutical [100,159,160]. This potentially bodes well for such intervention strategies even if there is considerable contribution to aging from low-level molecular noise and damage, but will require advances in the emerging computational methods to infer bioelectric interventions [161].

Atavistic genetic expression dissociation with age suggests that expressing evolutionarily-younger genes may relocate cells lost in phylogenetic space too allowing the cells to re-align on higher morphogenetic goals. Similarly, recent findins of inter-embryo communication that improves morphogenetic robustness [162] could expand existing work on parabiosis [163] and perhaps simulate the effect without needing to connect blood streams.

Finally, it is important to take even further the idea of top-down control over micromanagement. Where the bioelectric pattern renewal path seeks to re-write global setpoints, not micromanage cells or even genes, this can be taken further. Our “age-evidencing” hypothesis is that tissue-level age is not a physical or even biochemical parameter but the output result of cellular computations that integrate current state and past history of inputs [164,165]. It has already been noticed that when an organism is convinced to be older/younger [166], it behaves as such, including metrics at the cellular level, similarly to heterochronic parabiosis [167]. More recently, wild-type biobots made from un-modified adult epithelial cells from human patients experienced a rejuvenation event during the morphogenesis of their new form [168], which included a reversal of the epigenetic clock but not expression of reprogramming factors. This could be capitalized upon with stimuli that further push back cells’ estimates of their own age toward embryonic states without genetic induction of dangerous single genes, and may be related to similar rejuvenation events recently discovered during embryogenesis [169].

6. Conclusion

Aging is a complex field that has been addressed at multiple scales of spatial and temporal dynamics. We propose that the best hope we have of addressing this system-level limitation on our potential is to identify top-level mechanisms and policies which enable the Ship of Theseus that is our body to form and function in the first place. The future is likely not just micromanagement of molecular pathways but communication with the regulatory logic of complex bodies [17,22,170,171,172,173,174]. The loss of goal-directedness theory of aging suggests a specific roadmap: strengthen and perhaps re-write the pattern memories of healthy organs. Interfaces for such interventions include bioelectric, biochemical, biomechanical, and perhaps optical [175]. Future medicine of aging will merge with that of cancer and regenerative medicine aimed at large-scale restoration, likely drawing on all of the existing theories and approaches for a multi-faceted approach to tame this global, but ultimately surpassable, aspect of our current embodiment [176].

Table 1. Anti-aging treatments, targets, and their impact on aging.

Name of the intervention	Mechanistic Target	Rationale as anti-aging agent	Results/Observations/Outcome	Species/model	References
Cell reprogramming (partial/transient)/Stem cell rejuvenation
Yamanaka factors set of four transcription factors- Oct4, Sox2, Klf4 ± c-Myc (OSK or OSKM), ± senolytic peptide (Sen) ± senolytics dasatinib and quercetin (D+Q)	The four TFs work mechanistically by transient cellular reprogramming and stem cell rejuvenation. Senescent cells have persistently active mTOR pathway, leading to continuous secretion of proinflammatory cytokines and impaired tissue homeostasis. Synergetic combination of transient cellular reprogramming via OSKM factors and targeted removal of senescent cells by senolytic agents achieved lifespan and healthspan benefits.   In flies, lifespan extension seemed closely related to preservation of Intestinal Stem Cells (ISCs) in older flies (12 weeks) compared to control groups	Epigenetic dysregulation is amongst the underlying basis of aging that can be attenuated/reversed by epigenetic remodeling or cellular reprogramming. Approach is shown to extend lifespan, Improve healthspan (the duration of healthy life) by ameliorating age related diseases and reverse age-related changes in organs and tissues	Lifespan extension (mean and max) in m/f flies using short term pulsed expression of the four Yamanaka factors (102→122 days) + Sen (synergistic effect, 102→ 135 days) and Yamanaka TFs ± (D+Q); ~30% reduction in the initial mortality rate in flies   reversal of vision loss in an aged glaucoma mouse model by ectopic expression of OSK genes in retinal ganglion cells which restored younger DNA methylation patterns and promoted axon regeneration after injury   inducible systemic OSK -AAV in 124-week-old male mice extended the median remaining lifespan by 109% (133 → 142.5 days) over WT controls and enhanced health parameters such as frailty score (health span improvement).   transient expression of OSKM factors attenuated cellular and physiological hallmarks of aging and extended lifespan in a mouse model of premature aging. Expression of OSKM in vivo improved recovery from metabolic disease and muscle injury in older wild-type mice   exogenous OSK expression in human keratinocytes lead to significant reduction in epigenetic markers of age suggesting a potential rewiring of genetic networks to a younger healthier state	flies (Drosophila)   mouse   human keratinocytes   Worms (C.elegans)	[81,85,177,178,179]
Optimized Yamanaka factors (OSK) in conjunction with TERT (Telomerase Reverse Transcriptase) gene therapy	TERT mediated extension of telomeres that shorten with age; OSK expression lead to stem cell rejuvenation	Combined gene therapy proposed as a promising therapeutic strategy for extending lifespan and addressing aging-related diseases	In hu-MRC-5 cells, upregulated expression of youth-related genes- OCT4, SOX2, Klf4, Nanog, c-Myc, and TERT and the expression of aging-related genes- p16, p21, ZSCAN4, ATF3, and MMP13; the pro-inflammatory cytokine IL-6 and senescence-associated genes were significantly reduced	Human embryonic lung MRC-5 fibroblasts	[180]
Chemical cocktail induced partial reprogramming seven-compound (7c) - CHIR99021, DZNep, Forskolin, TTNPB, Valproic acid (VPA), Repsox, and Tranylcypromine (TCP) or two-compound (2c) reprogramming cocktail- Repsox and TCP	Chemical reprogramming modulated the underlying mechanisms and molecular hallmarks of aging such as improved age-associated DNA damage, epigenetic alterations, and induction of a unique transcriptomic profile enriched for developmental processes in aged human fibroblasts in vitro	Extension of both healthspan and lifespan via reversal of multiple aging hallmarks and induction towards a younger state in human fibroblasts	Dampening of aging phenotypes in dermal fibroblasts such as senescence, heterochromatin loss, genomic instability, and oxidative stress (ROS) with 7c cocktail, while 2c mixture retained rejuvenation effects   Median lifespan extension in worms by >42% (19 → 27 days), with improved stress resistance, thermotolerance, reproductive and healthspan markers with 2c cocktail	Worms (C.elegans)   Human fibroblasts and keratinocytes	[181]
Blood/Stem Cell mediated rejuvenation
Heterochronic parabiosis (HPB)/Heterochronic blood exchange (HBE)                                           Plasmapheresis or therapeutic plasma exchange (TPE) or plasma dilution                           Umbilical Cord (UC) Plasma transfusions	Inflammatory pathways modulated by the young plasma protein fraction included the PI3K-AkT, cytokine-cytokine receptor interaction, JAK-STAT, neurotrophin, NF-kappa B, and MAPK pathways                               TLR-4 was the node of the age-specific TPE-mediated rejuvenation of canonical signaling networks                           Decreased entropy in the methylation data, significant correlation between DNAm-based age acceleration and entropy-- decreased entropy may implicate the rejuvenation of the epigenetic landscape	The younger plasma infusion in elderly subjects influenced a range of biological processes associated with aging and age-related diseases (such as cancer, CVD), via regulation of inflammatory pathways and maybe particularly of interest for patients at risk of impaired and longer recovery time. These ‘younger blood factors’ may help dampen the inflammaging-associated inflammatory responses mediated by the adaptive immune system cells.     TPE-mediated recalibration of signaling pathways to younger state lead to improved homeostatic status of multiple organ systems.                           Plasma concentrate contains youth-promoting factors in the secretome of UC, administration of which resulted in nominally significant age-reversal effect revealed by DNA methylation clock DNAmGrimAge, an established robust epigenetic predictor of morbidity and mortality risk in humans	Infusion of GRF6021, an FDA approved 5% plasma protein fraction derived from younger donors (avg age~ 35y) to older patients (avg age~ 72 y) resulted in pathway and cell type specific anti-inflammatory immune-modulation in response to surgical injury; proteomics analysis and mass cytometry showed modulating effects on adaptive immune cell signaling- MAPK and JAK/STAT3 signaling responses in CD4 + and CD8 + T cells and regulatory T cell subsets were attenuated, while IkB (negative regulator of NFkB) was elevated               In a limited pilot study in humans, longitudinal effects of repeated TPE on systemic aging markers, a reduction in inflammaging and rejuvenation of age-specific systemic proteome was shown- diminished markers of neurodegeneration (TDP43) and cancer (increased P21 and p53), reduced senescence in PBMCs, lower DNA damage, decreased apoptotic inhibitors and improved myeloid/lymphoid homeostasis     Human umbilical cord plasma concentrate injected into elderly human subjects (mean age 74) and effect on different biomarkers, including epigenetic age, clinical biomarkers of organ dysfunction, mitochondrial DNA copy number (mtDNA-CN), and leukocyte telomere length were measured. Improved kidney function biomarkers were observed, telomere length and mtDNA-CN were not significantly affected, reduced DNA methylation-based GrimAge by an average of 0.82 years	Human subjects                                                             Human subjects                                         Human subjects	[182]                                                               [183]                                           [184]
HPB	Upregulated pathways for hematopoiesis, cytokine production, and stem cell population maintenance; restoration of cell-cell communications with cytokine/receptor interactions, chemotaxis, and leukocyte proliferation pathways enrichment       On the pathway level, global rescue of genes encoding electron transport chain (ETC) subunits indicated a mitochondrial function in parabiosis-mediated rejuvenation	Systemic revitalization of hematopoiesis by ‘young blood’ factors and restoration of dysregulated cytokine-mediated intercellular communication leading to younger transcriptional regulatory patterns                   Younger blood transfusion induced cellular and molecular programs that instructed systemic revitalization to re-establish youthful transcription/regulatory phenotypes	HP mediated rejuvenation of lymphopoiesis decline in aged HSCs, rejuvenated senile adult stem cells and their niches across tissues, restoration of youthful transcriptomes, reduced senescence-associated β-galactosidase (SA-β-gal)-positive cells in the spleen, skin, liver, and brain, decreased apoptotic cells in the spleen, skin, liver, and skeletal muscle       single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis revealed that ‘aged’ blood reduced global gene expression, and ‘young’ blood restored it in select cell types (adipose mesenchymal stromal cells, hematopoietic stem cells and hepatocytes)	mouse                                             mouse	[167]                                             [185]
HPB                                               Longer term HPB	Pro-aging factors in aged blood such as the chemokine CCL11/eotaxin and the inflammation related protein β2-microglobulin reduce neurogenesis, IL-6 and TGF-β impair hematopoiesis and the complement factor C1q compromises muscle repair; changed mitochondrial genes expression patterns involved in the electron transport chain (ETC)   Attenuation of inflammatory and interferon gamma (IFN-gamma) response gene sets, reduced pro-inflammatory phenotype; Gene expression changes mimicked longevity intervention signatures (such as median/ maximum lifespan and caloric restriction and growth hormone deficiency signatures)	restoration of regenerative capacity of old muscle with both parabiosis experiments (extrinsic effect) and transplantation of ex vivo-rejuvenated SCs into old animals (intrinsic effect)                                   long-term HPB acted on global scale affecting gene expression profiles, tissue methylation and systemic epigenomic remodeling leading to lifespan and healthspan extension	heterochronic parabiosis experiments followed by single-cell transcriptomics showed the soluble factors present in the blood of young mice restored renewal and repair capacity of muscles in old mice;   ‘young’ blood factors mediated rejuvenation and restoration of age-associated reduction in general gene expression, specifically the mitochondrial genes                     extended HPB (3 mo) resulted in sustained and systemic multi-omic rejuvenation effect, altered phenotype of older mice to intermediate (between old and young), reduced epigenetic age of blood and liver based on various clock models (RRBS based clocks such as Meer and Thompson multi-tissue methylation clocks, Petkovich blood clock, a maximum likelihood-based single-cell clock, array-specific epigenetic clocks- Universal, mouse blood/liver), a 6-week extension in median lifespan and a 2-week extension in maximum lifespan in old mice (compared to their isochronic controls) was observed.	Mouse                                                           mouse	[6,186,187]                                                         [188]
HBE- circulating Extracellular vesicles (EVs)	EVs improved muscle regeneration in a Klotho mRNA-dependent manner—a longevity protein at the intersection of Ca2+/K+ ion channel activity, mitochondrial function, and aging       Mechanistic investigations reveal that young sEVs stimulate PGC-1α expression in vitro and in vivo through their miRNA cargoes, thereby improving mitochondrial functions and mitigating mitochondrial deficits in aged tissues	young MuSCs are abundant in Klotho transcripts compared to aged MuSCs, loss of Klotho contributes to impaired MuSC mitochondrial ultrastructure and function over time, which can be reversed by exposure to young circulating EVs       substantial alterations in the proteomes of aged tissues after young sEV treatment that were closely associated with metabolic processes.   young sEVs reversed degenerative changes and age-related dysfunction, at least in part, by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism	Klotho mRNA within EVs contributed to functional skeletal muscle regeneration (in vivo) and enhanced mitochondrial function in MuSC progeny (in vitro)                   small extracellular vesicles (sEVs) from the plasma of young mice counteract pre-existing aging at molecular, mitochondrial, cellular and physiological levels   Intravenous injection of young sEVs into aged mice extended their lifespan, mitigated senescent phenotypes and ameliorated age-associated functional declines in multiple tissues	mouse	[189]                                 [82]
VEGF	reduced VEGF signaling and increased production of soluble VEGFR1 (sVEGFR1) due to an age-related shift in alternative splicing of VEGFR1 mRNA acting as a VEGF trap	vascular theory of aging- age related decrease of vascular function is a driver of systemic organismal aging and an upstream driver of multiorgan malfunctioning, hence mitigating it can potentially lead to comprehensive geroprotection	using a transgenic VEGF gain-of-function system or AAV–assisted VEGF transduction enhanced VEGF levels leading to a more youthful VEGF signaling, protection from age-related capillary loss, compromised perfusion, and reduced tissue oxygenation. Aging hallmarks such as mitochondrial dysfunction, compromised metabolic flexibility, endothelial cell senescence, and inflammaging were alleviated in VEGF-treated mice, which had an extended health span, as reflected by reduced abdominal fat accumulation, reduced liver steatosis, reduced muscle and bone loss (sarcopenia, osteoporosis) and reduced burden of spontaneous tumors	mouse	[190]
Extracellular Matrix (ECM)	In human fibroblasts, ‘young’ ECM mediated rejuvenation involved Ku-SIRT1 interaction, which are part of cell’s DNA damage and genome stability maintenance package     In C. elegans- proposed mechanism for increase in longevity involved pathway enrichment for chondroitin and heparan sulfate biogenesis and TGFβ pathway as predicted drug-protein targets	most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression or the ’matrisome’, ECM from young human fibroblasts induced a youthful state in aged senescent cells   C. elegans-- restored age-related decline of collagen homeostasis with increased lifespan, measured by collagen biosynthesis.	hu fibroblasts-- cell morphology, phenotypic restoration was assessed by resumption of proliferative potential, growth factor responsiveness, reduction of intracellular reactive oxygen species levels, recovery of mitochondrial membrane potential, and increased telomere length   ECM compounds such as chondroitin sulfate and hyaluronic acid restore the age-related decline of collagen and increase lifespan in nematodes;   In mice, deletion of chondroitin 6-sulfotransferase results in an abnormal ECM in the brain, early memory loss, and accelerated brain aging	C. elegans   human cells   mouse	[6,191,192]
Senolytics
Fisetin (3,3’,4’,7-tetrahydroxyflavone)	Direct antioxidant activity via enhanced glutathione levels, inhibited Lipoxygenases decreasing the production of pro-inflammatory factors/ eicosanoids; lifespan extension in worms mediated by DAF-16-induced stress response and autophagy	Mitigation of age-related accumulation of oxidative damage (free radical theory of aging), anti-inflammatory, and anti-tumor effect neuroprotective, restored tissue homeostasis in animal models	Reduced senescence markers in murine and human adipose tissues, reduced the cellular ROS levels and increased the resistance to oxidative stress and extended median and maximum lifespan in worms, improved high-glucose diet induced reduction in motility, reduced Amyloid beta-induced toxicity, inhibited degeneration of dopaminergic neurons in a PD model	C.elegans   murine and human fibroblasts	[193,194,195]
Dasatinib and Quercetin (D/Q) and Navitoclax	Pan-TK and BCL2 family of proteins- BCLXL, BCL2 and BCLW; improved α-Klotho levels	elimination of senescent cells, α-Klotho is a geroprotective protein and declined levels play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential	increased α-Klotho in IPF, a disease linked to cellular senescence, reduction and clearance of senescent cells and SASP factors, induction of apoptosis of senescent cell-associated phenotypes (SCAPs), therapeutic activity in a wide range of murine disease models associated with senescence	mouse   human primary cells   Human/clinical trials	[6,195,196,197]
Senomorphs- Novel/Natural Molecules/Supplements
Resveratrol (3, 5, 4′-trihydroxy-trans-stilbene)	Allosteric activators of SIRT family of proteins (SIRT1), CR mimetic	multi-effector anti-aging benefits across species	improved adipose insulin signaling in middle-aged mice on a high-calorie diet leading to better health/survival and insulin sensitivity, increased mitochondrial number, and improved motor functions; in yeast- stimulated SIRT1, increased DNA stability and extended lifespan by 70% ;   in worms and fruit flies- extended lifespan without affecting reproduction;   in NHPs- suppressed body mass gain in obesity model, reversed age-associated proinflammatory phenotypes in vascular smooth muscle cells, prevented age-related DNA and RNA oxidative damage, reduced mitochondrial loss and promoted autophagy in skeletal muscle and enhanced cognitive performances;   humans- improved glucose metabolism and cardiovascular disease markers, reduced oxidative stress, inflammation, and cell death, neuroprotective, antidiabetic, antibacterial and anti-aging effects and delayed cognitive decline in Alzheimer’s disease patients	yeast monkey/NHPs mice flies Hu	[198,199,200,201,202,203,204]
Alpha-ketoglutarate (KGA)	Different mechanisms across species, such as inhibiting mTOR and ATP-synthase, modulating DNA and histone demethylation and reducing ROS formation;   flies--Activation of AMPK signaling, inhibition of mTOR pathway and ATP-synthase   worms- Inhibition of ATP-synthase;   mice--Enhancement of IL-10 production;   humans- Rejuvant® supplement lead to reduction of DNA methylation	KGA plays a crucial role in the cell energy metabolism, amino acid/protein synthesis, epigenetic regulation, stemness and differentiation, fertility and reproductive health, and cancer cell behaviors	reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, and decreased both DNA damage and inflammation.   AKG extended longevity in C. elegans by ∼50% and delayed age-related phenotypes and reduced oxygen consumption;   mice- lifespan extension up to 10% in female and 5% in male flies- lifespan extension up to 23% in female and 2.8% in male;   human- AKG has beneficial effects on skin hydration and barrier function in human; in clinical trials- Rejuvant® supplementation lead to lifespan extension of up to 6.98 years in females and 8.44 years in males (biological age), improved functioning of bone, muscle, pancreas, brain, fat, gut, and immune system was observed indicating an overall increase in health span	mouse human pig fly worms	[205,206]
Taurine (2-aminoethanesulfonic acid)	Taurine proposed to modulate nutrient sensing and proteostasis pathways, with enhanced (LC3A/B), an autophagy marker, suppression of senescence, suppressed adverse consequences of telomerase deficiency, affects epigenetic changes via DNA methylation patterns	in humans, lower circulating taurine and its metabolites are associated with multiple age-associated pathologies, and their abundance increases after an exercise regimen.   higher blood taurine and hypotaurine levels were associated with lower body mass index (BMI) and waist-to-hip ratio (WHR), and less abdominal fat, lower prevalence of type 2 diabetes, lower glucose levels and lower levels of the inflammation marker, C-reactive protein (CRP)	Taurine supplementation increased the median lifespan in mice by 10 -12%, and life expectancy at 28 months increased by 18- 25%; increased muscle mass endurance, coordination, and strength in taurine-treated female mice; enhanced cognitive function- reduced depression-like behavior and anxiety, and enhanced exploratory behavior and memory;   increased lifespan in worms by 10-23% ; improved health parameters in middle-aged non-human primates	mouse monkey worms human	[207]
NAD	NAD+/Sirtuin pathway modulated longevity through activation of mitochondrial UPR and FOXO signaling, NAD precursor NR activated the UPRmt and the prohibitin signaling pathway in inhibition of MuSC senescence;   sirtuin protein sir-2.1, activated by NAD+, induced the UPR(mt), leading to the nuclear translocation and activation of the FOXO transcription factor DAF-16, which promoted antioxidant protection and extends lifespan	strategies that conserve, replenish cellular NAD(+) may reprogram dysfunctional stem cells to enhance the life span in mammals	in aging mice, NR/NAD treatment protected from muscle degeneration, loss of muscle stem cells, prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmd(mdx)/J) mouse model of muscular dystrophy, was protective of neural and melanocyte stem cells leading to the extended life span of the NR-treated animals.   In worms, enhancing NAD+ availability extended lifespan acting through sir-2.1 proteins   In humans- NAD/NR exerted a lipid-lowering effect and is a treatment option for dyslipidemia. It acts as a ligand for the G–protein-coupled receptor GPR109a, which inhibits hepatosteatosis and the progression of atherosclerosis and other inflammatory conditions	mouse   human   C. elegans	[208,209,210,211]
Oxytocin	Improved myogenic progenitor cell proliferation via activation of the MAPK/ERK pathway;   effects of OXT in chronic isolation related cellular aging in voles are mediated by reduction in elevated glucocorticoids	combats or prevent skeletal muscle aging/sarcopenia, and mediates the regenerative potential of muscle stem cells	systemic administration of oxytocin improved muscle regeneration while inhibition of oxytocin signaling in young animals reduced muscle regeneration;   Oxytocin treatment diminished the increased glucocorticoid levels, oxidative damage, telomere degradation and anhedonia after six weeks of chronic isolation in female prairie voles	mouse   female prairie voles	[212,213,214]
Epitalon aka Epithalon or Epithalone, (tetrapeptide, Ala-Glu-Asp-Gly (AEDG))	Specific and nonspecific mechanisms including direct influence on melatonin synthesis, influencing the mRNA levels of interleukin-2, and enhancing the activity of various enzymes, including AChE, BuChE, and telomerase	potential geroprotective and neuroendocrine effects of Epitalon, resulting from its antioxidant, neuro-protective, and antimutagenic effects.   Shown to lead to reactivation of telomerase gene in somatic cells with the possibility of prolonging life span of cell populations/organism	clinical trials showed decreased (2-fold effect), functional age and cardiovascular aging with enhanced exercise tolerance in long-term treatment in elderly patients with accelerated aging. Elongates telomeres and induces telomerase activity in telomerase-negative human fetal fibroblast cultures	human	[215,216,217]
Drugs/Medicinal interventions/Pathway Modulators (Inhibitors/Activators)
Rapamycin/Rapalogs	primarily exerts effect by Inhibiting m/TOR pathway, mimics CR-initiated nutrient scarcity, affects cellular shift from anabolic processes to maintenance and repair pathways, autophagy induction, enhanced proteostasis and translation fidelity	geroprotective, affects multi-modal mechanisms associated with lifespan extension such as induction of autophagy, modulating proteostasis (see MoA)	decreased mTOR signaling extends lifespan by up to 20% in yeast, 19% in worms, 24% in flies, and 60% in mice; randomized controlled trials showed reversal of immunosenescence and enhanced immune response following flu vaccines in older adults	mouse   human	[75,89,218,219,220]
Metformin	AMPK/LKB1 pathway activator, upregulation of pro-longevity signaling in Nrf2-GPx7 mediated antioxidant response	GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence; metformin-Nrf2-GPx7 pathway delays aging in worms, geroprotective effects on NHP neurons via the activation of Nrf2/anti-oxidant pathway	worms- extended median lifespan and promoted youthful mobility;   monkey- decelerated aging in males with reduction of aging markers, neuroprotective effect, with~6-year regression in brain aging, reduced oxidative damage and chronic inflammation;   humans- exerted effects by modulating multiple pro-aging pathways such as metabolic pathways, collagen trimerization and extracellular matrix (ECM) remodeling, adipose tissue and fatty acid metabolism, mitochondria, and the MutS genes (DNA mismatch repair)	C. elegans   Cynomolgus monkey   human cells	[221,222,223,224,225]
Sodium-glucose cotransporter 2 inhibitors (SGLT2-i such as dapagliflozin, canagliflozin, empagliflozin)	modulation of major nutrient-sensing pathways-upregulation of the energy deprivation sensors AMPK by shifting the AMP/ATP balance in favor of AMP and SIRT1, inhibition of the nutrient sensors mTOR and insulin/IGF1, and modulate the closely linked hypoxia-inducible factor (HIF)-2α/HIF-1α pathways; induces metabolic shift at the systemic level, promoting ketones and fatty acids utilization as energy source, lowers glucose by promoting its elimination through urine; CR mimetic	shown to ameliorate inflammaging in clinical trials, effects of SGLT-2i proposed to be mediated by their ability to attenuate the drivers of aging	Cardio and reno-protective effect in clinical trials against aging related major adverse cardiovascular (CV) events, heart failure, CV-related death, all-cause mortality, and renal outcomes in patients with or without diabetes;   increased mean lifespan mice fed on a long-term high-fat diet with reduction of inflammation, oxidative stress, and cellular senescence in visceral adipose tissue.	human   mouse	[226,227,228,229]
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) (albiglutide, dulaglutide, liraglutide, semaglutide, exenatide and lixisenatide	pleiotropic mechanisms of action- protects against cell apoptosis via the PI3K/Akt/mTOR/redox signaling pathway, protects beta cells against apoptosis and prevents beta-cell glucolipotoxicity via AMPK/mTOR signaling, enhances the DNA repair through the stimulation of APE1 expression, protects against apoptosis and inhibits ROS production via Sirt1 pathway, Liraglutide ameliorates mitochondrial dysfunction via AMP/PKA pathway; modulates cellular senescence through AMPK/SIRT1/FOXO3a pathway	protective against major hallmarks of aging such as oxidative stress, cellular senescence and chronic inflammation and related diseases	Cardio and neuro and reno-protective effect due to strong hypoglycemic action, lowered lipid levels, maintained blood pressure;     increased pancreatic insulin, GLUT2, and glucokinase mRNA, improved insulin response and glucose clearance in old rats, ameliorated muscle wasting, skeletal muscle atrophy and enhanced myogenesis, cardio, neuro and muscle protective roles demonstrated in rodent models	human   rodents	[230,231,232,233,234,235]
Sapanisertib	mTORC1/2 dual inhibitor	attenuated chronological aging in aged zebrafish and replicative senescence in HFF fibroblasts, potential for treating premature aging and promoting healthy aging	exerted superior effect in ameliorating cellular senescence compared to rapamycin in Zebrafish wrnKO, effect on aging phenotypes- inhibited SA-β-Gal activity (senescence), reduced the p21 and p53, improved swimming activity (primary indicator of healthspan); increased the proliferative capacity of the intestine and kidney marrow in aged zebrafish;   increased the cell proliferation rate of HFF cells, reduced SA-β-Gal staining	Zebrafish,   human cells—replicative senescent HFF	[236]
Trametinib	reversibly inhibits the MEK1 and MEK2 kinases within the MAPK pathway; increases translation accuracy	suppression of the insulin–IGF–mTORC1–Ras network ameliorates aging in animals	extended lifespan in flies;   improved translation fidelity, geroprotector in mice, extended lifespan in both sexes in mice	fly   mouse	[218,237]
Proteostasis modulator RPS23-K60R mutant	enhances translational fidelity and improves protein homeostasis and promotes damaged protein degradation	part of the ribosomal ‘accuracy center’, leads to proteostasis, one of the major hallmarks of aging	genetic manipulation of the ribosomal protein RPS23 to improve the accuracy of RNA-to-protein translation extended lifespan across organisms, and imparted heat shock resistance	yeast   flies   worms	[6,218]
Life Style/Diet Interventions
Calorie (CR) and Dietary restriction (DR)/ Intermittent Fasting (IF)	Beneficial effects are primarily mediated by increased activity of SIRT family of proteins, leading to modulated transcriptional programs implicated in mitochondrial metabolism, anti-inflammatory responses, and longevity, deletion of SIRT1 prevents longevity extension by CR in budding yeast, worms, and flies;   Another proposed mechanism is by reduction of PLA2G7 levels mediate the positive effects of caloric restriction (CR), such as improved metabolic health, reduced inflammation and longer health span;   In mice and rhesus monkeys, age-related methylation drift correlated with lifespan and CR attenuated negative impacts of it;   Nutrient sensing pathways respond to reduced glucose levels and increase AMPK activity with decreased mTORC1 signaling   Rats on IF/EOD exhibited slower growth rate, reduced weight and retarded development, perhaps trade off for the enhanced lifespan	over-expression of SIRT1 or SIRT6 in mice mimics physiological effects observed in CR and exercise, and extends lifespan, SIRT proteins protected against obesity, cancer, neurodegeneration, frailty, and a range of cardiometabolic conditions in monkeys and in humans;                 reduction of PLA2G7 levels may lead to immunometabolic effects of CR and could potentially be modulated to lower inflammation and extend the health span                                                                   Reduced feeding frequency directly improved lifespan in rats.	CR delayed aging, improved metabolic profile and lowered age-related morbidity risk in Rh monkeys by >two-fold;   22-30 years-old rhesus monkeys exposed to 30% caloric restriction showed attenuation of age-related methylation drift (blood methylation age ~ 7 years younger than chronologic age) compared to ad libitum-fed controls, more pronounced effects were seen in 2.7-3.2-year-old mice exposed to 40% caloric restriction. The effects of caloric restriction on DNA methylation were detectable across different tissues and correlated with gene expression;   intermittent fasting regimens have been reported to extend Drosophila lifespan by 15%–20%;   In humans- fasting and CR/DR shown to have strong associations with decreased rates of age-related disease and mortality in longitudinal studies, and from observational studies and randomized clinical trials, analyses of healthy humans aged 25–45 years of age, with sustained CR for two years showed enhanced thymic function, reduction of ectopic lipid, increased functional thymic volume, and increase in recent thymic emigrants in CD4 and CD8 T cells in blood.                 In rats, IF (every-other-day/EOD) resulted in reduced tumor formation, better long-term activity levels and significant lifespan enhancement, upto 83% (`124 weeks vs 103 weeks in ad libitum diet group).   DR shown to increase median and maximum lifespan in rats (average increase in median lifespan by 14–45% and maximum lifespan of 32.3%) and mice (average increase in median lifespan by 4–27% and maximum lifespan of ~18%)	NHPs   rodents   flies yeast   Hu Rat mouse	[90,200,202,238,239,240,241,242,243]
Amino Acids/Protein restriction	protein restriction (PR) and reduction in amino acids such as Methionine and Arginine and the branched-chain amino acids impact the activity of AKT, FOXO, mTOR, NAD+, AMPK and fibroblast growth factor 21 (FGF21), the key components of geroprotective signaling pathways	nutrient sensing pathways are affected (MoA) that promote healthy longevity	Human clinical trials--- PR reduces weight and adipose mass, and improve blood glucose regulation, in overweight individuals and people with type 2 diabetes;   restriction of protein has been shown to extend the lifespan in flies and rodents	human   flies   rodents	[6,242]
Specialized Diets, Exercise, Meditation and Social Interactions
Mediterranean	Cardio-protective and myo-protective effects by yet to characterize mechanisms, the diet components of unsaturated fat, polyphenols and phytosterols (EVOO, nuts, vegetables, fatty fish) activate the AMPK and sirtuin pathways, while mTOR is inhibited and autophagy is stimulated (EVOO increases mRNA levels of the autophagy marker LC3 in older rats); reduction of LDL-C levels by inhibition of cholesterol intestinal absorption and by blocking proprotein convertase subtilisin/kexin-9 (PCSK9). Role in improving mitochondrial metabolism; improvement of immune system dysregulation by micronutrients and ω-3 fatty acids (EPA and DHA), beneficial effects on microbiota diversity, activity and composition	cardio-protective and myo-protective effects prevent an excessive reduction of muscle mass and strength related to aging, hence exert positive effect on healthspan	myoprotective mechanism involved in ameliorating muscle ageing and sarcopenia, with higher bone mineral density; Cardioprotective effect shown in long-term clinical trials with reduction of cardiovascular disease (CVD), favorable effects on insulin sensitivity, blood pressure, lipid profiles, lipoprotein particles, oxidative stress, inflammation, and carotid atherosclerosis, lower inflammatory response	rodents   human	[6,244,245]
Ketogenic diet	Pleiotropic mode of action, mediated via formation of ketone bodies such as 3-hydroxybutyrate which may influence aging by acting as an energy substrate and alternative to glucose, through protein acetylation or β-hydroxybutyrylation, or via inhibition of histone deacetylase. It induces vasodilatation and activates immune responses acting on GTP protein coupled receptor 109A (GPR109A), with direct inhibition of the NLRP3 inflammasome	β-hydroxybutyrate inhibits the NLRP3 inflammasome and a ketogenic diet mitigates age-related increases in pro-inflammatory cytokines; this inhibition of inflammation may play a role in the extension of healthspan and longevity with a ketogenic diet	13.6% increase in median lifespan in mice with a significant decrease in histiocytic sarcomas, improvement in motor function and memory Studies of mice on an intermittent ketogenic diet fed every other week showed improvement in healthspan in aged animals	Mouse	[6,242]
Exercise	Multiple pathways affected, signaling cascades include IGF1, IL-6/JAK/STAT3, hippo and SIRT1 pathways;   Hippo signaling through YAP and Taz has been demonstrated to play a role in satellite cell activation and proliferation;   increased levels of taurine and taurine-related metabolites might mediate some of the health benefits of exercise.	beneficial impact on age related muscular impairment.   Exercise triggered increased levels of taurine metabolites in blood lead to antiaging effects of exercise. Mammalian SIRT1, SIRT3 and SIRT6 proposed to mediate the positive effects of exercise, while their genetic ablation prevents the benefits	exercise shown to impart multiple benefits to overall health, including improved bone and muscle strength, offset obesity, improved cardiovascular, cognitive and immune system functions;   human strength training (single/long-term) sessions resulted in a marked induction of muscle satellite stem cell activation and proliferation, activation of the muscle stem cell pool, increased mitochondrial numbers and quality, enhanced innervation by neuromuscular junctions, stimulate fibroapidogenic progenitors, (FAPs), and stimulate satellite cells to activate muscle repair and growth, leading to enhanced muscle strength and functioning.	mouse   rat   human	[195,207,246,247,248,249]
Mind-body therapies (MBT) tai chi, qigong, meditation, mindfulness, or yoga	stress management and reduced inflammation via reduced signaling of the proinflammatory NF-κB pathway and increased anti-inflammatory GR signaling	shown to be effective in improving sleep, reducing stress and improving quality of life, with possible impact on inflammation	26 randomized controlled trials showed the effects of mind-body therapies (MBTs) on circulating, cellular, and genomic markers of inflammation with mixed effects on circulating inflammatory markers, such as CRP and IL-6, decreased expression of inflammation-related genes and reduced signaling through the proinflammatory transcription factor NF-κB	human	[250]
Family/Relationships and Social Interactions	the hypothalamic neuropeptide oxytocin (OXT) has been proposed to play an important role; chronic isolation leads to elevated glucocorticoids, which can affect cellular mechanisms of aging, including increased levels of oxidative stress and shortened telomere lengths	poor social support leads to accelerated aging and is associated with reduced telomere length. Happy relationships, intimacy and family/social support is associated with increased immunity, better overall health, and a longer lifespan	Oxytocin treatment diminished the increased glucocorticoid levels, oxidative damage, telomere degradation and anhedonia after six weeks of chronic isolation	female prairie voles humans	[213,214]
Several clinical trials are in progress to measure benefits/impacts of multi-modal anti-aging interventions.					[230,251,252,253]
Mind-body therapies (MBT) tai chi, qigong, meditation, mindfulness, or yoga	stress management and reduced inflammation via reduced signaling of the proinflammatory NF-κB pathway and increased anti-inflammatory GR signaling	shown to be effective in improving sleep, reducing stress and improving quality of life, with possible impact on inflammation	26 randomized controlled trials showed the effects of mind-body therapies (MBTs) on circulating, cellular, and genomic markers of inflammation with mixed effects on circulating inflammatory markers, such as CRP and IL-6, decreased expression of inflammation-related genes and reduced signaling through the proinflammatory transcription factor NF-κB	human	[250]
Family/Relationships and Social Interactions	the hypothalamic neuropeptide oxytocin (OXT) has been proposed to play an important role; chronic isolation leads to elevated glucocorticoids, which can affect cellular mechanisms of aging, including increased levels of oxidative stress and shortened telomere lengths	poor social support leads to accelerated aging and is associated with reduced telomere length. Happy relationships, intimacy and family/social support is associated with increased immunity, better overall health, and a longer lifespan	Oxytocin treatment diminished the increased glucocorticoid levels, oxidative damage, telomere degradation and anhedonia after six weeks of chronic isolation	female prairie voles humans	[213,214]
Several clinical trials are in progress to measure benefits/impacts of multi-modal anti-aging interventions.					[230,251,252,253]
Experimental anti-aging treatments
Rejuvenating CD4+ T-cells	CD4+ T-cells	youthful immune signaling improve tissue maintenance and resilience by delivering ‘rivers of telomerase’	transferring young or metabolically reprogrammed CD4+ T cells into aged mice triggered telomere-river production, and isolated rivers could be transplanted to reproduce the rejuvenation effect.	rodents	[88]

Table 1. Anti-aging treatments, targets, and their impact on aging.

Name of the intervention	Mechanistic Target	Rationale as anti-aging agent	Results/Observations/Outcome	Species/model	References
Cell reprogramming (partial/transient)/Stem cell rejuvenation
Yamanaka factors set of four transcription factors- Oct4, Sox2, Klf4 ± c-Myc (OSK or OSKM), ± senolytic peptide (Sen) ± senolytics dasatinib and quercetin (D+Q)	The four TFs work mechanistically by transient cellular reprogramming and stem cell rejuvenation. Senescent cells have persistently active mTOR pathway, leading to continuous secretion of proinflammatory cytokines and impaired tissue homeostasis. Synergetic combination of transient cellular reprogramming via OSKM factors and targeted removal of senescent cells by senolytic agents achieved lifespan and healthspan benefits.   In flies, lifespan extension seemed closely related to preservation of Intestinal Stem Cells (ISCs) in older flies (12 weeks) compared to control groups	Epigenetic dysregulation is amongst the underlying basis of aging that can be attenuated/reversed by epigenetic remodeling or cellular reprogramming. Approach is shown to extend lifespan, Improve healthspan (the duration of healthy life) by ameliorating age related diseases and reverse age-related changes in organs and tissues	Lifespan extension (mean and max) in m/f flies using short term pulsed expression of the four Yamanaka factors (102→122 days) + Sen (synergistic effect, 102→ 135 days) and Yamanaka TFs ± (D+Q); ~30% reduction in the initial mortality rate in flies   reversal of vision loss in an aged glaucoma mouse model by ectopic expression of OSK genes in retinal ganglion cells which restored younger DNA methylation patterns and promoted axon regeneration after injury   inducible systemic OSK -AAV in 124-week-old male mice extended the median remaining lifespan by 109% (133 → 142.5 days) over WT controls and enhanced health parameters such as frailty score (health span improvement).   transient expression of OSKM factors attenuated cellular and physiological hallmarks of aging and extended lifespan in a mouse model of premature aging. Expression of OSKM in vivo improved recovery from metabolic disease and muscle injury in older wild-type mice   exogenous OSK expression in human keratinocytes lead to significant reduction in epigenetic markers of age suggesting a potential rewiring of genetic networks to a younger healthier state	flies (Drosophila)   mouse   human keratinocytes   Worms (C.elegans)	[81,85,177,178,179]
Optimized Yamanaka factors (OSK) in conjunction with TERT (Telomerase Reverse Transcriptase) gene therapy	TERT mediated extension of telomeres that shorten with age; OSK expression lead to stem cell rejuvenation	Combined gene therapy proposed as a promising therapeutic strategy for extending lifespan and addressing aging-related diseases	In hu-MRC-5 cells, upregulated expression of youth-related genes- OCT4, SOX2, Klf4, Nanog, c-Myc, and TERT and the expression of aging-related genes- p16, p21, ZSCAN4, ATF3, and MMP13; the pro-inflammatory cytokine IL-6 and senescence-associated genes were significantly reduced	Human embryonic lung MRC-5 fibroblasts	[180]
Chemical cocktail induced partial reprogramming seven-compound (7c) - CHIR99021, DZNep, Forskolin, TTNPB, Valproic acid (VPA), Repsox, and Tranylcypromine (TCP) or two-compound (2c) reprogramming cocktail- Repsox and TCP	Chemical reprogramming modulated the underlying mechanisms and molecular hallmarks of aging such as improved age-associated DNA damage, epigenetic alterations, and induction of a unique transcriptomic profile enriched for developmental processes in aged human fibroblasts in vitro	Extension of both healthspan and lifespan via reversal of multiple aging hallmarks and induction towards a younger state in human fibroblasts	Dampening of aging phenotypes in dermal fibroblasts such as senescence, heterochromatin loss, genomic instability, and oxidative stress (ROS) with 7c cocktail, while 2c mixture retained rejuvenation effects   Median lifespan extension in worms by >42% (19 → 27 days), with improved stress resistance, thermotolerance, reproductive and healthspan markers with 2c cocktail	Worms (C.elegans)   Human fibroblasts and keratinocytes	[181]
Blood/Stem Cell mediated rejuvenation
Heterochronic parabiosis (HPB)/Heterochronic blood exchange (HBE)                                           Plasmapheresis or therapeutic plasma exchange (TPE) or plasma dilution                           Umbilical Cord (UC) Plasma transfusions	Inflammatory pathways modulated by the young plasma protein fraction included the PI3K-AkT, cytokine-cytokine receptor interaction, JAK-STAT, neurotrophin, NF-kappa B, and MAPK pathways                               TLR-4 was the node of the age-specific TPE-mediated rejuvenation of canonical signaling networks                           Decreased entropy in the methylation data, significant correlation between DNAm-based age acceleration and entropy-- decreased entropy may implicate the rejuvenation of the epigenetic landscape	The younger plasma infusion in elderly subjects influenced a range of biological processes associated with aging and age-related diseases (such as cancer, CVD), via regulation of inflammatory pathways and maybe particularly of interest for patients at risk of impaired and longer recovery time. These ‘younger blood factors’ may help dampen the inflammaging-associated inflammatory responses mediated by the adaptive immune system cells.     TPE-mediated recalibration of signaling pathways to younger state lead to improved homeostatic status of multiple organ systems.                           Plasma concentrate contains youth-promoting factors in the secretome of UC, administration of which resulted in nominally significant age-reversal effect revealed by DNA methylation clock DNAmGrimAge, an established robust epigenetic predictor of morbidity and mortality risk in humans	Infusion of GRF6021, an FDA approved 5% plasma protein fraction derived from younger donors (avg age~ 35y) to older patients (avg age~ 72 y) resulted in pathway and cell type specific anti-inflammatory immune-modulation in response to surgical injury; proteomics analysis and mass cytometry showed modulating effects on adaptive immune cell signaling- MAPK and JAK/STAT3 signaling responses in CD4 + and CD8 + T cells and regulatory T cell subsets were attenuated, while IkB (negative regulator of NFkB) was elevated               In a limited pilot study in humans, longitudinal effects of repeated TPE on systemic aging markers, a reduction in inflammaging and rejuvenation of age-specific systemic proteome was shown- diminished markers of neurodegeneration (TDP43) and cancer (increased P21 and p53), reduced senescence in PBMCs, lower DNA damage, decreased apoptotic inhibitors and improved myeloid/lymphoid homeostasis     Human umbilical cord plasma concentrate injected into elderly human subjects (mean age 74) and effect on different biomarkers, including epigenetic age, clinical biomarkers of organ dysfunction, mitochondrial DNA copy number (mtDNA-CN), and leukocyte telomere length were measured. Improved kidney function biomarkers were observed, telomere length and mtDNA-CN were not significantly affected, reduced DNA methylation-based GrimAge by an average of 0.82 years	Human subjects                                                             Human subjects                                         Human subjects	[182]                                                               [183]                                           [184]
HPB	Upregulated pathways for hematopoiesis, cytokine production, and stem cell population maintenance; restoration of cell-cell communications with cytokine/receptor interactions, chemotaxis, and leukocyte proliferation pathways enrichment       On the pathway level, global rescue of genes encoding electron transport chain (ETC) subunits indicated a mitochondrial function in parabiosis-mediated rejuvenation	Systemic revitalization of hematopoiesis by ‘young blood’ factors and restoration of dysregulated cytokine-mediated intercellular communication leading to younger transcriptional regulatory patterns                   Younger blood transfusion induced cellular and molecular programs that instructed systemic revitalization to re-establish youthful transcription/regulatory phenotypes	HP mediated rejuvenation of lymphopoiesis decline in aged HSCs, rejuvenated senile adult stem cells and their niches across tissues, restoration of youthful transcriptomes, reduced senescence-associated β-galactosidase (SA-β-gal)-positive cells in the spleen, skin, liver, and brain, decreased apoptotic cells in the spleen, skin, liver, and skeletal muscle       single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis revealed that ‘aged’ blood reduced global gene expression, and ‘young’ blood restored it in select cell types (adipose mesenchymal stromal cells, hematopoietic stem cells and hepatocytes)	mouse                                             mouse	[167]                                             [185]
HPB                                               Longer term HPB	Pro-aging factors in aged blood such as the chemokine CCL11/eotaxin and the inflammation related protein β2-microglobulin reduce neurogenesis, IL-6 and TGF-β impair hematopoiesis and the complement factor C1q compromises muscle repair; changed mitochondrial genes expression patterns involved in the electron transport chain (ETC)   Attenuation of inflammatory and interferon gamma (IFN-gamma) response gene sets, reduced pro-inflammatory phenotype; Gene expression changes mimicked longevity intervention signatures (such as median/ maximum lifespan and caloric restriction and growth hormone deficiency signatures)	restoration of regenerative capacity of old muscle with both parabiosis experiments (extrinsic effect) and transplantation of ex vivo-rejuvenated SCs into old animals (intrinsic effect)                                   long-term HPB acted on global scale affecting gene expression profiles, tissue methylation and systemic epigenomic remodeling leading to lifespan and healthspan extension	heterochronic parabiosis experiments followed by single-cell transcriptomics showed the soluble factors present in the blood of young mice restored renewal and repair capacity of muscles in old mice;   ‘young’ blood factors mediated rejuvenation and restoration of age-associated reduction in general gene expression, specifically the mitochondrial genes                     extended HPB (3 mo) resulted in sustained and systemic multi-omic rejuvenation effect, altered phenotype of older mice to intermediate (between old and young), reduced epigenetic age of blood and liver based on various clock models (RRBS based clocks such as Meer and Thompson multi-tissue methylation clocks, Petkovich blood clock, a maximum likelihood-based single-cell clock, array-specific epigenetic clocks- Universal, mouse blood/liver), a 6-week extension in median lifespan and a 2-week extension in maximum lifespan in old mice (compared to their isochronic controls) was observed.	Mouse                                                           mouse	[6,186,187]                                                         [188]
HBE- circulating Extracellular vesicles (EVs)	EVs improved muscle regeneration in a Klotho mRNA-dependent manner—a longevity protein at the intersection of Ca2+/K+ ion channel activity, mitochondrial function, and aging       Mechanistic investigations reveal that young sEVs stimulate PGC-1α expression in vitro and in vivo through their miRNA cargoes, thereby improving mitochondrial functions and mitigating mitochondrial deficits in aged tissues	young MuSCs are abundant in Klotho transcripts compared to aged MuSCs, loss of Klotho contributes to impaired MuSC mitochondrial ultrastructure and function over time, which can be reversed by exposure to young circulating EVs       substantial alterations in the proteomes of aged tissues after young sEV treatment that were closely associated with metabolic processes.   young sEVs reversed degenerative changes and age-related dysfunction, at least in part, by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism	Klotho mRNA within EVs contributed to functional skeletal muscle regeneration (in vivo) and enhanced mitochondrial function in MuSC progeny (in vitro)                   small extracellular vesicles (sEVs) from the plasma of young mice counteract pre-existing aging at molecular, mitochondrial, cellular and physiological levels   Intravenous injection of young sEVs into aged mice extended their lifespan, mitigated senescent phenotypes and ameliorated age-associated functional declines in multiple tissues	mouse	[189]                                 [82]
VEGF	reduced VEGF signaling and increased production of soluble VEGFR1 (sVEGFR1) due to an age-related shift in alternative splicing of VEGFR1 mRNA acting as a VEGF trap	vascular theory of aging- age related decrease of vascular function is a driver of systemic organismal aging and an upstream driver of multiorgan malfunctioning, hence mitigating it can potentially lead to comprehensive geroprotection	using a transgenic VEGF gain-of-function system or AAV–assisted VEGF transduction enhanced VEGF levels leading to a more youthful VEGF signaling, protection from age-related capillary loss, compromised perfusion, and reduced tissue oxygenation. Aging hallmarks such as mitochondrial dysfunction, compromised metabolic flexibility, endothelial cell senescence, and inflammaging were alleviated in VEGF-treated mice, which had an extended health span, as reflected by reduced abdominal fat accumulation, reduced liver steatosis, reduced muscle and bone loss (sarcopenia, osteoporosis) and reduced burden of spontaneous tumors	mouse	[190]
Extracellular Matrix (ECM)	In human fibroblasts, ‘young’ ECM mediated rejuvenation involved Ku-SIRT1 interaction, which are part of cell’s DNA damage and genome stability maintenance package     In C. elegans- proposed mechanism for increase in longevity involved pathway enrichment for chondroitin and heparan sulfate biogenesis and TGFβ pathway as predicted drug-protein targets	most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression or the ’matrisome’, ECM from young human fibroblasts induced a youthful state in aged senescent cells   C. elegans-- restored age-related decline of collagen homeostasis with increased lifespan, measured by collagen biosynthesis.	hu fibroblasts-- cell morphology, phenotypic restoration was assessed by resumption of proliferative potential, growth factor responsiveness, reduction of intracellular reactive oxygen species levels, recovery of mitochondrial membrane potential, and increased telomere length   ECM compounds such as chondroitin sulfate and hyaluronic acid restore the age-related decline of collagen and increase lifespan in nematodes;   In mice, deletion of chondroitin 6-sulfotransferase results in an abnormal ECM in the brain, early memory loss, and accelerated brain aging	C. elegans   human cells   mouse	[6,191,192]
Senolytics
Fisetin (3,3’,4’,7-tetrahydroxyflavone)	Direct antioxidant activity via enhanced glutathione levels, inhibited Lipoxygenases decreasing the production of pro-inflammatory factors/ eicosanoids; lifespan extension in worms mediated by DAF-16-induced stress response and autophagy	Mitigation of age-related accumulation of oxidative damage (free radical theory of aging), anti-inflammatory, and anti-tumor effect neuroprotective, restored tissue homeostasis in animal models	Reduced senescence markers in murine and human adipose tissues, reduced the cellular ROS levels and increased the resistance to oxidative stress and extended median and maximum lifespan in worms, improved high-glucose diet induced reduction in motility, reduced Amyloid beta-induced toxicity, inhibited degeneration of dopaminergic neurons in a PD model	C.elegans   murine and human fibroblasts	[193,194,195]
Dasatinib and Quercetin (D/Q) and Navitoclax	Pan-TK and BCL2 family of proteins- BCLXL, BCL2 and BCLW; improved α-Klotho levels	elimination of senescent cells, α-Klotho is a geroprotective protein and declined levels play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential	increased α-Klotho in IPF, a disease linked to cellular senescence, reduction and clearance of senescent cells and SASP factors, induction of apoptosis of senescent cell-associated phenotypes (SCAPs), therapeutic activity in a wide range of murine disease models associated with senescence	mouse   human primary cells   Human/clinical trials	[6,195,196,197]
Senomorphs- Novel/Natural Molecules/Supplements
Resveratrol (3, 5, 4′-trihydroxy-trans-stilbene)	Allosteric activators of SIRT family of proteins (SIRT1), CR mimetic	multi-effector anti-aging benefits across species	improved adipose insulin signaling in middle-aged mice on a high-calorie diet leading to better health/survival and insulin sensitivity, increased mitochondrial number, and improved motor functions; in yeast- stimulated SIRT1, increased DNA stability and extended lifespan by 70% ;   in worms and fruit flies- extended lifespan without affecting reproduction;   in NHPs- suppressed body mass gain in obesity model, reversed age-associated proinflammatory phenotypes in vascular smooth muscle cells, prevented age-related DNA and RNA oxidative damage, reduced mitochondrial loss and promoted autophagy in skeletal muscle and enhanced cognitive performances;   humans- improved glucose metabolism and cardiovascular disease markers, reduced oxidative stress, inflammation, and cell death, neuroprotective, antidiabetic, antibacterial and anti-aging effects and delayed cognitive decline in Alzheimer’s disease patients	yeast monkey/NHPs mice flies Hu	[198,199,200,201,202,203,204]
Alpha-ketoglutarate (KGA)	Different mechanisms across species, such as inhibiting mTOR and ATP-synthase, modulating DNA and histone demethylation and reducing ROS formation;   flies--Activation of AMPK signaling, inhibition of mTOR pathway and ATP-synthase   worms- Inhibition of ATP-synthase;   mice--Enhancement of IL-10 production;   humans- Rejuvant® supplement lead to reduction of DNA methylation	KGA plays a crucial role in the cell energy metabolism, amino acid/protein synthesis, epigenetic regulation, stemness and differentiation, fertility and reproductive health, and cancer cell behaviors	reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, and decreased both DNA damage and inflammation.   AKG extended longevity in C. elegans by ∼50% and delayed age-related phenotypes and reduced oxygen consumption;   mice- lifespan extension up to 10% in female and 5% in male flies- lifespan extension up to 23% in female and 2.8% in male;   human- AKG has beneficial effects on skin hydration and barrier function in human; in clinical trials- Rejuvant® supplementation lead to lifespan extension of up to 6.98 years in females and 8.44 years in males (biological age), improved functioning of bone, muscle, pancreas, brain, fat, gut, and immune system was observed indicating an overall increase in health span	mouse human pig fly worms	[205,206]
Taurine (2-aminoethanesulfonic acid)	Taurine proposed to modulate nutrient sensing and proteostasis pathways, with enhanced (LC3A/B), an autophagy marker, suppression of senescence, suppressed adverse consequences of telomerase deficiency, affects epigenetic changes via DNA methylation patterns	in humans, lower circulating taurine and its metabolites are associated with multiple age-associated pathologies, and their abundance increases after an exercise regimen.   higher blood taurine and hypotaurine levels were associated with lower body mass index (BMI) and waist-to-hip ratio (WHR), and less abdominal fat, lower prevalence of type 2 diabetes, lower glucose levels and lower levels of the inflammation marker, C-reactive protein (CRP)	Taurine supplementation increased the median lifespan in mice by 10 -12%, and life expectancy at 28 months increased by 18- 25%; increased muscle mass endurance, coordination, and strength in taurine-treated female mice; enhanced cognitive function- reduced depression-like behavior and anxiety, and enhanced exploratory behavior and memory;   increased lifespan in worms by 10-23% ; improved health parameters in middle-aged non-human primates	mouse monkey worms human	[207]
NAD	NAD+/Sirtuin pathway modulated longevity through activation of mitochondrial UPR and FOXO signaling, NAD precursor NR activated the UPRmt and the prohibitin signaling pathway in inhibition of MuSC senescence;   sirtuin protein sir-2.1, activated by NAD+, induced the UPR(mt), leading to the nuclear translocation and activation of the FOXO transcription factor DAF-16, which promoted antioxidant protection and extends lifespan	strategies that conserve, replenish cellular NAD(+) may reprogram dysfunctional stem cells to enhance the life span in mammals	in aging mice, NR/NAD treatment protected from muscle degeneration, loss of muscle stem cells, prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmd(mdx)/J) mouse model of muscular dystrophy, was protective of neural and melanocyte stem cells leading to the extended life span of the NR-treated animals.   In worms, enhancing NAD+ availability extended lifespan acting through sir-2.1 proteins   In humans- NAD/NR exerted a lipid-lowering effect and is a treatment option for dyslipidemia. It acts as a ligand for the G–protein-coupled receptor GPR109a, which inhibits hepatosteatosis and the progression of atherosclerosis and other inflammatory conditions	mouse   human   C. elegans	[208,209,210,211]
Oxytocin	Improved myogenic progenitor cell proliferation via activation of the MAPK/ERK pathway;   effects of OXT in chronic isolation related cellular aging in voles are mediated by reduction in elevated glucocorticoids	combats or prevent skeletal muscle aging/sarcopenia, and mediates the regenerative potential of muscle stem cells	systemic administration of oxytocin improved muscle regeneration while inhibition of oxytocin signaling in young animals reduced muscle regeneration;   Oxytocin treatment diminished the increased glucocorticoid levels, oxidative damage, telomere degradation and anhedonia after six weeks of chronic isolation in female prairie voles	mouse   female prairie voles	[212,213,214]
Epitalon aka Epithalon or Epithalone, (tetrapeptide, Ala-Glu-Asp-Gly (AEDG))	Specific and nonspecific mechanisms including direct influence on melatonin synthesis, influencing the mRNA levels of interleukin-2, and enhancing the activity of various enzymes, including AChE, BuChE, and telomerase	potential geroprotective and neuroendocrine effects of Epitalon, resulting from its antioxidant, neuro-protective, and antimutagenic effects.   Shown to lead to reactivation of telomerase gene in somatic cells with the possibility of prolonging life span of cell populations/organism	clinical trials showed decreased (2-fold effect), functional age and cardiovascular aging with enhanced exercise tolerance in long-term treatment in elderly patients with accelerated aging. Elongates telomeres and induces telomerase activity in telomerase-negative human fetal fibroblast cultures	human	[215,216,217]
Drugs/Medicinal interventions/Pathway Modulators (Inhibitors/Activators)
Rapamycin/Rapalogs	primarily exerts effect by Inhibiting m/TOR pathway, mimics CR-initiated nutrient scarcity, affects cellular shift from anabolic processes to maintenance and repair pathways, autophagy induction, enhanced proteostasis and translation fidelity	geroprotective, affects multi-modal mechanisms associated with lifespan extension such as induction of autophagy, modulating proteostasis (see MoA)	decreased mTOR signaling extends lifespan by up to 20% in yeast, 19% in worms, 24% in flies, and 60% in mice; randomized controlled trials showed reversal of immunosenescence and enhanced immune response following flu vaccines in older adults	mouse   human	[75,89,218,219,220]
Metformin	AMPK/LKB1 pathway activator, upregulation of pro-longevity signaling in Nrf2-GPx7 mediated antioxidant response	GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence; metformin-Nrf2-GPx7 pathway delays aging in worms, geroprotective effects on NHP neurons via the activation of Nrf2/anti-oxidant pathway	worms- extended median lifespan and promoted youthful mobility;   monkey- decelerated aging in males with reduction of aging markers, neuroprotective effect, with~6-year regression in brain aging, reduced oxidative damage and chronic inflammation;   humans- exerted effects by modulating multiple pro-aging pathways such as metabolic pathways, collagen trimerization and extracellular matrix (ECM) remodeling, adipose tissue and fatty acid metabolism, mitochondria, and the MutS genes (DNA mismatch repair)	C. elegans   Cynomolgus monkey   human cells	[221,222,223,224,225]
Sodium-glucose cotransporter 2 inhibitors (SGLT2-i such as dapagliflozin, canagliflozin, empagliflozin)	modulation of major nutrient-sensing pathways-upregulation of the energy deprivation sensors AMPK by shifting the AMP/ATP balance in favor of AMP and SIRT1, inhibition of the nutrient sensors mTOR and insulin/IGF1, and modulate the closely linked hypoxia-inducible factor (HIF)-2α/HIF-1α pathways; induces metabolic shift at the systemic level, promoting ketones and fatty acids utilization as energy source, lowers glucose by promoting its elimination through urine; CR mimetic	shown to ameliorate inflammaging in clinical trials, effects of SGLT-2i proposed to be mediated by their ability to attenuate the drivers of aging	Cardio and reno-protective effect in clinical trials against aging related major adverse cardiovascular (CV) events, heart failure, CV-related death, all-cause mortality, and renal outcomes in patients with or without diabetes;   increased mean lifespan mice fed on a long-term high-fat diet with reduction of inflammation, oxidative stress, and cellular senescence in visceral adipose tissue.	human   mouse	[226,227,228,229]
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) (albiglutide, dulaglutide, liraglutide, semaglutide, exenatide and lixisenatide	pleiotropic mechanisms of action- protects against cell apoptosis via the PI3K/Akt/mTOR/redox signaling pathway, protects beta cells against apoptosis and prevents beta-cell glucolipotoxicity via AMPK/mTOR signaling, enhances the DNA repair through the stimulation of APE1 expression, protects against apoptosis and inhibits ROS production via Sirt1 pathway, Liraglutide ameliorates mitochondrial dysfunction via AMP/PKA pathway; modulates cellular senescence through AMPK/SIRT1/FOXO3a pathway	protective against major hallmarks of aging such as oxidative stress, cellular senescence and chronic inflammation and related diseases	Cardio and neuro and reno-protective effect due to strong hypoglycemic action, lowered lipid levels, maintained blood pressure;     increased pancreatic insulin, GLUT2, and glucokinase mRNA, improved insulin response and glucose clearance in old rats, ameliorated muscle wasting, skeletal muscle atrophy and enhanced myogenesis, cardio, neuro and muscle protective roles demonstrated in rodent models	human   rodents	[230,231,232,233,234,235]
Sapanisertib	mTORC1/2 dual inhibitor	attenuated chronological aging in aged zebrafish and replicative senescence in HFF fibroblasts, potential for treating premature aging and promoting healthy aging	exerted superior effect in ameliorating cellular senescence compared to rapamycin in Zebrafish wrnKO, effect on aging phenotypes- inhibited SA-β-Gal activity (senescence), reduced the p21 and p53, improved swimming activity (primary indicator of healthspan); increased the proliferative capacity of the intestine and kidney marrow in aged zebrafish;   increased the cell proliferation rate of HFF cells, reduced SA-β-Gal staining	Zebrafish,   human cells—replicative senescent HFF	[236]
Trametinib	reversibly inhibits the MEK1 and MEK2 kinases within the MAPK pathway; increases translation accuracy	suppression of the insulin–IGF–mTORC1–Ras network ameliorates aging in animals	extended lifespan in flies;   improved translation fidelity, geroprotector in mice, extended lifespan in both sexes in mice	fly   mouse	[218,237]
Proteostasis modulator RPS23-K60R mutant	enhances translational fidelity and improves protein homeostasis and promotes damaged protein degradation	part of the ribosomal ‘accuracy center’, leads to proteostasis, one of the major hallmarks of aging	genetic manipulation of the ribosomal protein RPS23 to improve the accuracy of RNA-to-protein translation extended lifespan across organisms, and imparted heat shock resistance	yeast   flies   worms	[6,218]
Life Style/Diet Interventions
Calorie (CR) and Dietary restriction (DR)/ Intermittent Fasting (IF)	Beneficial effects are primarily mediated by increased activity of SIRT family of proteins, leading to modulated transcriptional programs implicated in mitochondrial metabolism, anti-inflammatory responses, and longevity, deletion of SIRT1 prevents longevity extension by CR in budding yeast, worms, and flies;   Another proposed mechanism is by reduction of PLA2G7 levels mediate the positive effects of caloric restriction (CR), such as improved metabolic health, reduced inflammation and longer health span;   In mice and rhesus monkeys, age-related methylation drift correlated with lifespan and CR attenuated negative impacts of it;   Nutrient sensing pathways respond to reduced glucose levels and increase AMPK activity with decreased mTORC1 signaling   Rats on IF/EOD exhibited slower growth rate, reduced weight and retarded development, perhaps trade off for the enhanced lifespan	over-expression of SIRT1 or SIRT6 in mice mimics physiological effects observed in CR and exercise, and extends lifespan, SIRT proteins protected against obesity, cancer, neurodegeneration, frailty, and a range of cardiometabolic conditions in monkeys and in humans;                 reduction of PLA2G7 levels may lead to immunometabolic effects of CR and could potentially be modulated to lower inflammation and extend the health span                                                                   Reduced feeding frequency directly improved lifespan in rats.	CR delayed aging, improved metabolic profile and lowered age-related morbidity risk in Rh monkeys by >two-fold;   22-30 years-old rhesus monkeys exposed to 30% caloric restriction showed attenuation of age-related methylation drift (blood methylation age ~ 7 years younger than chronologic age) compared to ad libitum-fed controls, more pronounced effects were seen in 2.7-3.2-year-old mice exposed to 40% caloric restriction. The effects of caloric restriction on DNA methylation were detectable across different tissues and correlated with gene expression;   intermittent fasting regimens have been reported to extend Drosophila lifespan by 15%–20%;   In humans- fasting and CR/DR shown to have strong associations with decreased rates of age-related disease and mortality in longitudinal studies, and from observational studies and randomized clinical trials, analyses of healthy humans aged 25–45 years of age, with sustained CR for two years showed enhanced thymic function, reduction of ectopic lipid, increased functional thymic volume, and increase in recent thymic emigrants in CD4 and CD8 T cells in blood.                 In rats, IF (every-other-day/EOD) resulted in reduced tumor formation, better long-term activity levels and significant lifespan enhancement, upto 83% (`124 weeks vs 103 weeks in ad libitum diet group).   DR shown to increase median and maximum lifespan in rats (average increase in median lifespan by 14–45% and maximum lifespan of 32.3%) and mice (average increase in median lifespan by 4–27% and maximum lifespan of ~18%)	NHPs   rodents   flies yeast   Hu Rat mouse	[90,200,202,238,239,240,241,242,243]
Amino Acids/Protein restriction	protein restriction (PR) and reduction in amino acids such as Methionine and Arginine and the branched-chain amino acids impact the activity of AKT, FOXO, mTOR, NAD+, AMPK and fibroblast growth factor 21 (FGF21), the key components of geroprotective signaling pathways	nutrient sensing pathways are affected (MoA) that promote healthy longevity	Human clinical trials--- PR reduces weight and adipose mass, and improve blood glucose regulation, in overweight individuals and people with type 2 diabetes;   restriction of protein has been shown to extend the lifespan in flies and rodents	human   flies   rodents	[6,242]
Specialized Diets, Exercise, Meditation and Social Interactions
Mediterranean	Cardio-protective and myo-protective effects by yet to characterize mechanisms, the diet components of unsaturated fat, polyphenols and phytosterols (EVOO, nuts, vegetables, fatty fish) activate the AMPK and sirtuin pathways, while mTOR is inhibited and autophagy is stimulated (EVOO increases mRNA levels of the autophagy marker LC3 in older rats); reduction of LDL-C levels by inhibition of cholesterol intestinal absorption and by blocking proprotein convertase subtilisin/kexin-9 (PCSK9). Role in improving mitochondrial metabolism; improvement of immune system dysregulation by micronutrients and ω-3 fatty acids (EPA and DHA), beneficial effects on microbiota diversity, activity and composition	cardio-protective and myo-protective effects prevent an excessive reduction of muscle mass and strength related to aging, hence exert positive effect on healthspan	myoprotective mechanism involved in ameliorating muscle ageing and sarcopenia, with higher bone mineral density; Cardioprotective effect shown in long-term clinical trials with reduction of cardiovascular disease (CVD), favorable effects on insulin sensitivity, blood pressure, lipid profiles, lipoprotein particles, oxidative stress, inflammation, and carotid atherosclerosis, lower inflammatory response	rodents   human	[6,244,245]
Ketogenic diet	Pleiotropic mode of action, mediated via formation of ketone bodies such as 3-hydroxybutyrate which may influence aging by acting as an energy substrate and alternative to glucose, through protein acetylation or β-hydroxybutyrylation, or via inhibition of histone deacetylase. It induces vasodilatation and activates immune responses acting on GTP protein coupled receptor 109A (GPR109A), with direct inhibition of the NLRP3 inflammasome	β-hydroxybutyrate inhibits the NLRP3 inflammasome and a ketogenic diet mitigates age-related increases in pro-inflammatory cytokines; this inhibition of inflammation may play a role in the extension of healthspan and longevity with a ketogenic diet	13.6% increase in median lifespan in mice with a significant decrease in histiocytic sarcomas, improvement in motor function and memory Studies of mice on an intermittent ketogenic diet fed every other week showed improvement in healthspan in aged animals	Mouse	[6,242]
Exercise	Multiple pathways affected, signaling cascades include IGF1, IL-6/JAK/STAT3, hippo and SIRT1 pathways;   Hippo signaling through YAP and Taz has been demonstrated to play a role in satellite cell activation and proliferation;   increased levels of taurine and taurine-related metabolites might mediate some of the health benefits of exercise.	beneficial impact on age related muscular impairment.   Exercise triggered increased levels of taurine metabolites in blood lead to antiaging effects of exercise. Mammalian SIRT1, SIRT3 and SIRT6 proposed to mediate the positive effects of exercise, while their genetic ablation prevents the benefits	exercise shown to impart multiple benefits to overall health, including improved bone and muscle strength, offset obesity, improved cardiovascular, cognitive and immune system functions;   human strength training (single/long-term) sessions resulted in a marked induction of muscle satellite stem cell activation and proliferation, activation of the muscle stem cell pool, increased mitochondrial numbers and quality, enhanced innervation by neuromuscular junctions, stimulate fibroapidogenic progenitors, (FAPs), and stimulate satellite cells to activate muscle repair and growth, leading to enhanced muscle strength and functioning.	mouse   rat   human	[195,207,246,247,248,249]
Mind-body therapies (MBT) tai chi, qigong, meditation, mindfulness, or yoga	stress management and reduced inflammation via reduced signaling of the proinflammatory NF-κB pathway and increased anti-inflammatory GR signaling	shown to be effective in improving sleep, reducing stress and improving quality of life, with possible impact on inflammation	26 randomized controlled trials showed the effects of mind-body therapies (MBTs) on circulating, cellular, and genomic markers of inflammation with mixed effects on circulating inflammatory markers, such as CRP and IL-6, decreased expression of inflammation-related genes and reduced signaling through the proinflammatory transcription factor NF-κB	human	[250]
Family/Relationships and Social Interactions	the hypothalamic neuropeptide oxytocin (OXT) has been proposed to play an important role; chronic isolation leads to elevated glucocorticoids, which can affect cellular mechanisms of aging, including increased levels of oxidative stress and shortened telomere lengths	poor social support leads to accelerated aging and is associated with reduced telomere length. Happy relationships, intimacy and family/social support is associated with increased immunity, better overall health, and a longer lifespan	Oxytocin treatment diminished the increased glucocorticoid levels, oxidative damage, telomere degradation and anhedonia after six weeks of chronic isolation	female prairie voles humans	[213,214]
Several clinical trials are in progress to measure benefits/impacts of multi-modal anti-aging interventions.					[230,251,252,253]
Mind-body therapies (MBT) tai chi, qigong, meditation, mindfulness, or yoga	stress management and reduced inflammation via reduced signaling of the proinflammatory NF-κB pathway and increased anti-inflammatory GR signaling	shown to be effective in improving sleep, reducing stress and improving quality of life, with possible impact on inflammation	26 randomized controlled trials showed the effects of mind-body therapies (MBTs) on circulating, cellular, and genomic markers of inflammation with mixed effects on circulating inflammatory markers, such as CRP and IL-6, decreased expression of inflammation-related genes and reduced signaling through the proinflammatory transcription factor NF-κB	human	[250]
Family/Relationships and Social Interactions	the hypothalamic neuropeptide oxytocin (OXT) has been proposed to play an important role; chronic isolation leads to elevated glucocorticoids, which can affect cellular mechanisms of aging, including increased levels of oxidative stress and shortened telomere lengths	poor social support leads to accelerated aging and is associated with reduced telomere length. Happy relationships, intimacy and family/social support is associated with increased immunity, better overall health, and a longer lifespan	Oxytocin treatment diminished the increased glucocorticoid levels, oxidative damage, telomere degradation and anhedonia after six weeks of chronic isolation	female prairie voles humans	[213,214]
Several clinical trials are in progress to measure benefits/impacts of multi-modal anti-aging interventions.					[230,251,252,253]
Experimental anti-aging treatments
Rejuvenating CD4+ T-cells	CD4+ T-cells	youthful immune signaling improve tissue maintenance and resilience by delivering ‘rivers of telomerase’	transferring young or metabolically reprogrammed CD4+ T cells into aged mice triggered telomere-river production, and isolated rivers could be transplanted to reproduce the rejuvenation effect.	rodents	[88]