Healthy Life Function: A Hypothesis We Are Not Programmed to Age. We Are Programmed to Live

1. Introduction

The prevailing view of aging as an inevitable, time-dependent process has misguided scientific inquiry for decades [60,77]. This paradigm assumes a programmed biological decline, yet no clear genetic mandate for aging has been identified [75]. We propose a fundamental shift: what is traditionally called “aging” is not a distinct process but the consequence of a treatable pathology we term Healthy Life Function Dysregulation (HLFD). HLFD is a syndrome of systemic imbalance, characterized by the decline of key regulatory factors (most notably the protein Klotho), leading to metabolic inefficiencies, immune dysfunction, and impaired cellular life cycle [44,94]. Unlike aging, HLFD is not driven by chronology but by the failure of active maintenance, offering a new target for intervention. Life’s design prioritizes persistence and reproduction, not decline. DNA’s theoretical immortality (evidenced by its endurance in ancient fossils) [140] and the indefinite renewal of species like Hydra [96] underscore this principle. Biological systems thrive through dynamic regulation, combating entropy via self-repair and metabolic equilibrium [121]. When this regulation falters, as in HLFD, the symptoms misattributed to aging emerge [48].

Klotho, a pleiotropic hormone, emerges as a critical regulator in this framework. Its decline correlates with systemic dysregulation, while its presence supports metabolic, immune, and reproductive health [81]. Stressors such as exercise or fasting, often lauded for longevity benefits, may enhance Klotho expression in skeletal muscle [9,149]. This paper challenges the focus on slowing “aging” and advocates redirecting research toward sustaining healthy life function. By treating HLFD, potentially through novel interventions like mRNA Klotho therapy, we aim to restore physiological balance and extend healthspan, aligning with life’s inherent programming to endure rather than fade [67]. Examples of nature’s long-lived organisms, detailed later, reinforce this hypothesis: life persists where regulation thrives.

Defining HLFD

HLFD is a syndrome of systemic imbalance, marked by declining Klotho [81], faltering repair [94], and reproductive fade [22], that manifests as what we call “aging.” It is not time-driven but a failure of active maintenance [44], measurable via biomarkers like Klotho levels (<600 pg/mL) [23], inflammation (IL-6) [44], and fertility markers [22]. We reframe aging as HLFD, targeting dysregulation over chronology.

2. There Is No Program for Aging: The Fundamental Paradigm Shift

Aging is not a biological process in the conventional sense; it is not a pathogen or a morbidity we can treat with standard interventions [75]. It is a misclassification of system failure [48]. Moreover, the symptoms we identify as aging are not chronologically dependent [40]. Medicine has spent decades attempting to slow, reverse, or prevent aging, treating it as if it were an inevitable disease [31]. This paper challenges that premise entirely: aging, as a standalone process, is not programmed into our biology [77]. Instead, all biological decline results from Healthy Life Function Dysregulation (HLFD), a failure of systemic regulation that can be identified, characterized as a novel syndrome, and corrected [44]. Nobel Laureate Venki Ramakrishnan supports this paradigm, arguing that aging is not programmed but a byproduct of evolutionary neglect post-reproduction, aligning with our view that HLFD, not time, drives decline [157]. Rather than researching ways to reverse “aging,” we propose that the focus must shift to maintaining the regulatory equilibrium that sustains life [67].

Table 1. Theories of Aging and Their Relation to HLFD.

Theory	Description	Relation to HLFD	Reference
Wear and Tear	Aging as physical breakdown over time	Misinterprets systemic dysregulation as time	[57]
Free Radical Theory	Damage from oxidative stress causes aging	Links to HLFD via Klotho’s antioxidant role	[119]
HLFD (Proposed)	Systemic dysregulation, not time-dependent	Targets Klotho as one of the most promising tools	[80,82]

Table 1. Theories of Aging and Their Relation to HLFD.

Theory	Description	Relation to HLFD	Reference
Wear and Tear	Aging as physical breakdown over time	Misinterprets systemic dysregulation as time	[57]
Free Radical Theory	Damage from oxidative stress causes aging	Links to HLFD via Klotho’s antioxidant role	[119]
HLFD (Proposed)	Systemic dysregulation, not time-dependent	Targets Klotho as one of the most promising tools	[80,82]

3. The Miracle of Life: The Base State of Matter Is Abiotic

The default state of matter is abiotic, lifeless [121]. Life does not emerge passively from inanimate matter; rather, it requires an explosive, highly dynamic process, driven by energy-intensive reactions, like ATP synthesis, to transition into a biological system [84]. From the moment of conception, life occurs not as a gradual unfolding but as an aggressive metabolic event that demands continuous energy, molecular coordination, and systemic regulation to sustain itself [102]. Unlike inert matter, biological systems must actively fight entropy through self-repair, homeostasis, and metabolic equilibrium [121]. The failure to maintain this balance leads to biological dysfunction, which has been misinterpreted as a chronological facet of life [48]. Instead of attempting to push back an inevitable decline, the goal should be to sustain the life-supporting regulatory mechanisms that keep life vital [84]. Life’s code endures unless damaged, and repair systems like Klotho [81], telomerase [15], and sirtuins [66] keep it thriving. Life’s drive is not to fade; HLFD is the glitch. Practices like exercise [9], fasting [149], or UV exposure [63], seen as beneficial, stress the system; Klotho’s surge and other triggered repair mechanisms deliver the life-supporting benefits, not the stressors [81].

4. Creation: Growth Cycles of Human Organisms

Life progresses in distinct phases of growth and regulation rather than a simple linear aging process [40]. These include:

• Conception to Birth: Rapid cellular division, highest metabolic rates, and extreme stem cell activity [50].
• Birth to Age 2: Fast growth rate, highest energy utilization per body weight [83].
• Childhood (2–12 years): Slower but stable growth, robust immune function [124].
• Puberty (12–18 years): Hormonal surge, peak regenerative capacity, and the onset of reproductive capability [16].
• Healthy Life Plateau (18–35 years): Maximum metabolic efficiency, peak reproductive and systemic health [23].
• Post-Plateau (35+ years): The system remains functional if regulatory mechanisms like Klotho remain stable; otherwise, HLFD develops [80].

This model reinforces that life consists of regulated biological states, each requiring precise control to sustain function [40]. These phases reflect life’s programming to live [29]. DNA fuels growth and repair, not decline [148]. Klotho stabilizes at the plateau, supporting telomerase (telomere length) [38], SIRT6 (DNA repair) [101], NAD+ (energy) [66], and stem cell activity (regeneration) [92]. Centenarians’ higher Klotho shows time does not mandate HLFD [69]. Naked mole rats, breeding into their 30s [17], and Picea abies (Old Tjikko), cloning for 9,550 years [79], show life’s phases can extend indefinitely with repair and reproductive continuity [121]. Could Klotho mirror this in humans? [81]

5. The Combustive Nature of Life: Cellular Turnover and Health: Our Cells ARE Programmed to Die so that We May Remain Renewed

Cellular turnover underpins the combustive process of a healthy functioning system. Our cells are programmed to die [6]. Current longevity strategies often focus on slowing metabolism and prolonging cellular lifespan through interventions like fasting [97] and senolytics [74]. However, we propose that health and longevity depend on aggressive and constant cellular turnover and metabolic activity, catalyzed by Klotho [81]. Healthy Life Function depends on a combustive process where cells rapidly grow, divide, die, and are cleared [112]. This aligns with the youthful state of high metabolic activity, where rapid cell renewal maintains function, resilience, and vitality [112]. Ramakrishnan’s work on ribosomes reveals how protein synthesis errors accumulate with damage, contributing to cellular dysfunction [157]. This supports our argument that HLFD arises from impaired turnover, which Klotho mitigates via AMPK activation and mTORC1 inhibition [158, 159]. Slowing this process may lead to stagnation, dysfunction, and disease [94]. “Aging” is typically associated with cellular decline, and many longevity interventions aim to preserve cells for longer periods [76]. However, youthfulness is characterized by a high metabolic rate and rapid cell turnover, not cellular preservation [112]. The traditional view assumes that slowing cellular activity reduces damage accumulation [57], but this ignores the fundamental importance of continuous renewal for maintaining function [6].

5.1. Cellular Turnover as the Foundation of Health

The Young Metabolism: High Turnover, High Function

• Young individuals exhibit rapid cell proliferation, differentiation, and clearance [6].
• High mitochondrial activity supports fast energy production, fueling this renewal cycle [84].
• Growth hormone and anabolic signaling pathways (e.g., mTOR, IGF-1) are active, promoting tissue regeneration [126].
• Decline in cellular turnover with age is linked to degeneration, immune dysfunction, and disease [94].

The Essential Role of Cell Death and Clearance

• Apoptosis removes dysfunctional cells, preventing cancer and systemic dysfunction [73].
• Autophagy recycles cellular components, maintaining cellular efficiency [99].
• Phagocytosis clears dead cells, preventing toxic accumulation [114].
• When these processes slow, senescent cells accumulate, secreting inflammatory factors (SASP) that contribute to aging and chronic disease [20].

5.2. The Problem with Longevity Strategies That Slow Metabolism

Fasting: A Preservation Strategy That Opposes Turnover

• Fasting suppresses mTOR and growth signals, reducing cell proliferation and turnover [97].
• It promotes quiescence, slowing metabolism and reducing energy expenditure [43].
• While fasting increases autophagy temporarily [99], it does not enhance total cellular replacement; it merely delays turnover [10].
• In contrast, “young” individuals’ systems that are functioning properly thrive on continuous metabolic activity, not prolonged energy conservation [112]. This healthy metabolic activity appears to correlate with higher Klotho serum levels [23].

Senolytics: A Partial Solution That Ignores Regeneration

• Senolytics remove senescent cells, which is beneficial [74], but they do not stimulate robust new cell growth [150].
• A truly effective approach would actively promote new cell generation and clearance, maintaining a constant renewal cycle [112].
• Since we know that Klotho plays an important role in metabolic function [81], we advance the hypothesis that Klotho supplementation may be one major intervention to support Healthy Life Function regulation: “YOUTH” [82].

5.3. A New Model: Maintaining Cellular Turnover for Longevity

Instead of slowing metabolism and cellular activity, we should aim to support the natural combustive process of life by:

Promoting Anabolic and Catabolic Balance

• Encouraging cell proliferation through appropriate nutrient intake (protein, amino acids) [108].
• Enhancing autophagy and apoptosis through exercise, which naturally stimulates cellular clearance [61].
• Avoiding prolonged caloric restriction, which signals the body to conserve resources rather than renew tissue [43].
• Supplementing Klotho levels as they decline with age to keep them in the optimal range to support healthy, aggressive, and continuous metabolic function [23].

Supporting Mitochondrial and Metabolic Activity

• High mitochondrial turnover maintains energy production efficiency [136].
• Klotho serum level is essential for sustaining high metabolic activity [147].
• Avoiding interventions that downregulate metabolism (e.g., excessive fasting, long-term caloric restriction) [43].

Encouraging Phagocytosis and Immune Surveillance

• Optimizing immune function helps remove damaged cells effectively [114].
• Chronic low-grade inflammation (often seen with accumulated senescent cells) should be prevented through active clearance rather than mere suppression [44].
• Klotho is known to support phagocytosis and promote inflammation resolution [91].

We suggest that the key to health and longevity is not cellular preservation, but constant and aggressive cellular turnover, a process mirroring the high metabolic state of youth [112]. Our cells must continuously grow, divide, die, and renew to sustain optimal function [6]. While current longevity strategies focus on slowing this process, they may inadvertently contribute to cellular stagnation and dysfunction [94]. Future research should explore interventions that support rather than suppress cellular turnover, embracing the combustive nature of life as the path to sustained health and vitality [84].

6. Evidence That Aging Is Not Time-Dependent

Aging stems from dysregulation, not time [40].

6.1. Centenarians vs. Median Life Expectancy

A significant discrepancy exists in human longevity. While the current median human lifespan ranges between 70–80 years [139], this was not always the case. In pre-industrial times, average life expectancy was below 30 [24]; today, the median is 74 [135]. Increasingly, there are documented cases of individuals living beyond 110–120 years in good health [116]. Currently, there are nearly 800,000 centenarians worldwide, a number expected to quadruple by 2054 [134] (Note: This projection is an extrapolation from trends in [134]).

Table 2. Ten Oldest Verified Living Humans as of February 24, 2025.

Rank	Name	Age	Country	Reference
1	Inah Canabarro Lucas	116 years, 261 days	Brazil	[49]
2	Ethel Caterham	115 years, 187 days	United Kingdom	[49]
3	Okagi Hayashi	115 years, 175 days	Japan	[49]
4	Elizabeth Francis	115 years, 214 days	United States	[49]
5	Juan Vicente Pérez Mora	115 years, 273 days	Venezuela	[49]
6	Noeme da Silveira Freitas	115 years, 81 days	Brazil	[49]
7	Jeanne Bot	115 years, 41 days	France	[49]
8	João Marinho Neto	112 years, 142 days	Brazil	[49]
9	Eusebio Quintero López	111 years, 355 days	Colombia	[49]
10	Manuel Benavente Sanhueza	111 years, 341 days	Chile	[49]

Table 2. Ten Oldest Verified Living Humans as of February 24, 2025.

Rank	Name	Age	Country	Reference
1	Inah Canabarro Lucas	116 years, 261 days	Brazil	[49]
2	Ethel Caterham	115 years, 187 days	United Kingdom	[49]
3	Okagi Hayashi	115 years, 175 days	Japan	[49]
4	Elizabeth Francis	115 years, 214 days	United States	[49]
5	Juan Vicente Pérez Mora	115 years, 273 days	Venezuela	[49]
6	Noeme da Silveira Freitas	115 years, 81 days	Brazil	[49]
7	Jeanne Bot	115 years, 41 days	France	[49]
8	João Marinho Neto	112 years, 142 days	Brazil	[49]
9	Eusebio Quintero López	111 years, 355 days	Colombia	[49]
10	Manuel Benavente Sanhueza	111 years, 341 days	Chile	[49]

These extreme variations in lifespan demonstrate that biological longevity is not dictated by time but by the ability to maintain systemic regulation [41]. This healthspan phenomenon appears across races, cultures, and geographical locations, highlighting that encoded in human DNA is the potential, without intervention, to live healthily until at least 120–125 years [116]. How much longer could we achieve, if our efforts were focused correctly? 200? 300? Beyond? [8]. Correcting for war, birth mortality, and other factors, even our most successful median lifespan is nearly 40% shorter than this verified possible range [135].

We could theorize that our species has been afflicted by a pandemic since the beginning of time: most individuals will experience HLFD at some point [44]. Whether triggered by lifestyle choices [43], genetic factors [62], or environmental conditions [26], failing to recognize HLFD as the pathology leads science to misdirect its efforts, akin to treating a bacterial infection with bloodletting [111]. Before microbes were discovered, physicians believed the body’s four humors (blood, phlegm, black bile, yellow bile) needed balance, and infections stemmed from excess blood [111]. Once penicillin targeted microbes [42], our understanding shifted to address the actual pathogen. Similarly, HLFD requires a new focus on dysregulation as the root cause rather than chronological decline.

6.2. Examples of Non-Chronological Decline

Genetic conditions illustrate that what we call aging is not linked to chronology but a dysregulation of biological systems [40].

• Hutchinson-Gilford Progeria Syndrome (HGPS): HGPS causes children to develop aging-like features (wrinkled skin, cardiovascular disease, and joint stiffness) within years of birth due to LMNA gene mutations disrupting nuclear architecture [51]. This is not accelerated aging but systemic dysregulation from defective DNA repair and cellular maintenance [36]. Klotho’s role in phosphate homeostasis via FGF23 signaling could mitigate vascular calcification in HGPS, as patients exhibit mineral imbalances [65,51]. Its decline may exacerbate DNA damage, given Klotho’s protective effects on genomic stability through oxidative stress reduction [144].
• Werner Syndrome (WS): WS triggers rapid decline in early adulthood (osteoporosis, cardiovascular disease, and metabolic failure) due to WRN gene mutations impairing DNA helicase function [106]. This dysregulation mimics aging phenotypes, not time-driven decay [53]. Klotho’s depletion increases DNA damage post-radiation, suggesting it could worsen WS’s repair deficits [144]. Its regulation of phosphate via FGF23 may address WS’s osteoporosis and calcification [65]. Hypogonadism in 80% of WS patients, linked to gonadal atrophy, aligns with Klotho’s hormonal regulation via insulin signaling, hinting at a fertility-HLFD connection [22].
• Bloom Syndrome (BS): BS, caused by BLM gene mutations, impairs DNA helicase activity, leading to genomic instability [141]. Patients exhibit premature aging traits (skin atrophy, cancer predisposition) by their 20s, with lifespans averaging 30–40 years [142]. This reflects dysregulation, not time, as DNA repair fails early [143]. Klotho’s antioxidant role via Mn-SOD modulation could reduce BS’s oxidative stress, a key driver of chromosomal breaks and cellular damage [147].
• Cockayne Syndrome (CS): CS results from ERCC6/8 mutations, disrupting nucleotide excision repair, causing children to show aged features (neurodegeneration, hearing loss, skeletal defects) by age 5–10, with lifespans rarely exceeding 20 [154,155]. This is repair failure, not chronological aging. Klotho’s regulation of phosphate via FGF23 could mitigate CS’s osteopenia, a bone mineralization defect linked to repair stress [65], while its mitochondrial protection via PGC-1α may reduce neuronal oxidative damage [119,81].
• Klotho Knockout Mice: Mice lacking Klotho exhibit a 10-fold lifespan reduction, developing osteoporosis, arteriosclerosis, and frailty within weeks [80]. This systemic failure, not time-dependent aging, stems from absent phosphate regulation (via FGF23) and mitochondrial collapse [65]. Infertility due to undeveloped reproductive organs further ties HLFD to dysregulation [80]. Klotho supplementation reverses these effects, proving treatability [65].

These cases—HGPS, WS, BS, CS, and Klotho-deficient mice—collectively demonstrate that “aging” is a misnomer for biological dysregulation [40]. Klotho’s roles in phosphate homeostasis, DNA repair, and mitochondrial function underscore its potential to counter HLFD [81].

6.3. Microgravity: Spaceflight as an HLFD Model

Microgravity exemplifies HLFD, with systemic decline arising from the loss of gravity’s regulatory drive [40]. Astronauts Butch Wilmore and Suni Williams (286 days on the ISS, June 2024–March 2025) and Cosmonaut Valeri Polyakov (437 days on Mir, 1994–1995) experienced rapid deterioration: despite exercise, muscle atrophied at 1–2% monthly, bone density dropped up to 20%, and cardiovascular strain emerged from fluid shifts (2L upward) [52]. Radiation in microgravity increases oxidative stress, depleting antioxidant defenses like Mn-SOD, potentially linked to Klotho’s mitochondrial protection [147], accelerating HLFD-like bone and muscle loss [52]. Endocrine dysregulation reduced testosterone significantly, impairing sperm motility and risking ovarian function due to radiation and stress [125,129]. These changes, mimicking decades of “aging” in months, reversed upon Earth return: muscle regained 85–90% in weeks, cardio function in months, and bone 70–80% over several years [52]. Reproductive markers normalized within weeks to months [125].

6.4. NASA Twins Study: Microgravity’s Dysregulation with a Control

The NASA Twins Study provides a controlled comparison of microgravity’s effects, highlighting HLFD over chronological aging [156]. Astronaut Scott Kelly spent 340 days on the ISS (2015–2016), while his identical twin, Mark Kelly, remained on Earth as a genetic baseline. Scott exhibited rapid telomere shortening (average 14.5% reduction), muscle loss (up to 7% in legs), and gene expression shifts (e.g., upregulation of inflammation genes like IL-6, downregulation of DNA repair genes) mimicking aging phenotypes [156]. Bone density decreased 1–2% monthly, linked to disrupted phosphate metabolism, and endocrine changes lowered testosterone, reflecting systemic stress [125]. Mark, on Earth, showed stable telomeres, muscle mass, and gene expression over the same period, isolating microgravity as the dysregulation driver [156] and highlighting the need for the combustive process needed to exist in Earth’s gravity. Post-flight, Scott’s telomeres lengthened beyond pre-flight levels within months, muscle recovered, and most gene expression normalized, though some epigenetic changes (e.g., methylation patterns) persisted [156]. This reversibility mirrors HLFD’s treatability [40].

Klotho’s mechanistic role is critical: microgravity disrupts phosphate metabolism (linked to bone loss), oxidative balance (exacerbated by radiation), and hormonal homeostasis, processes Klotho regulates via FGF23 and mitochondrial support [81,65]. Knockout mice show parallel osteoporosis and infertility in weeks, reversed by supplementation restoring phosphate and mitochondrial function [80,65]. In space, Klotho’s decline could worsen HLFD, with recovery suggesting its rebound, urging pre/post-flight studies [81]. This rapid, reversible dysregulation reinforces that HLFD, not time, drives decline [40]. Future studies should quantify pre/post-flight Klotho levels to confirm its mechanistic role [81]. The twin-controlled evidence powerfully shows microgravity induces HLFD-like dysregulation, independent of chronological age [156].

7. Why Are We Here? The Purpose of Life

Biologically, there is only one purpose to life: to bring forth more life. Reproduction: the continuation of genetic material through successive generations [29]. Organisms were not created to age; we were created to reproduce [75]. Unlike outdated views that treat aging as a function of time [60], the ability to reproduce serves as a direct biological marker of systemic health [109]. Organisms do not “age” out of reproductive capacity; rather, they lose reproductive function due to regulatory failure [22]. We propose reproductive health, and its corresponding hormones, should be explored as another potential biomarker for the onset of HLFD.

7.1. Reproduction and Systemic Health

Biological organisms are designed for reproduction, and optimal health coincides with peak reproductive years [40]. The ability to reproduce requires a highly functional biological system, maintaining peak metabolic stability, immune response, and cellular repair [22]. As reproductive capacity diminishes, signs of HLFD emerge, supporting the argument that functional decline is caused by systemic dysregulation [44]. Reproductive longevity has been shown to correlate with overall longevity [109]:

• Women who conceive later in life tend to live longer, demonstrating that reproductive function is linked to systemic resilience; studies suggest genetic factors like telomere length may underlie this [109].
• Men with high testosterone and sperm motility show fewer age-related diseases, reinforcing that reproductive function is a marker of biological health; further research could quantify this link [71].
• Hormonal Links: Reproductive hormones (e.g., testosterone, estrogen) influence not just fertility but also muscle strength, immune function, and energy levels [14]. A drop in these hormones often signals broader decline [58].
• Cellular Aging: Reproductive cells are sensitive to stressors like oxidative damage or poor nutrition [5]. When these cells falter, it reflects a systemic breakdown, as cellular health underpins both reproduction and survival [4]. Interestingly, these same stressors trigger Klotho upregulation [81]. Research suggests that as long as the system can produce enough Klotho to protect from these disruptions, the system seems to repair itself and continue to function properly [22].
• Life Cycle Patterns: In many species, once reproductive capacity wanes (e.g., post-menopause in humans or senescence and even sudden death in other animals), overall health declines more rapidly [40].

7.2. Queen Bees and Dominant Reproducers: Living Long as Reproductive Systems

In species with social hierarchies, the queen bee is exemplary of reproduction and longevity’s dependency. The queen is the hive’s sole reproducer, and her workers, sterile females, dedicate their lives to her reproductive success [142]. The queen bee lives years, while workers last weeks, all because her reproduction is the colony’s purpose [123]. This pattern repeats elsewhere:

• Alpha Wolves: In wolf packs, the alpha pair dominates breeding. Subordinates hunt and guard the pups, supporting the alphas’ reproductive role. Alphas often live longer and healthier due to their status [98].
• Meerkats: The dominant female reproduces while subordinates care for her pups. Her health and longevity trump theirs [25].

In these species, the dominant reproducers’ extended, healthier lives are no accident. They are the linchpin of the group’s reproductive strategy [141]. The whole social system bends toward their fertility, proving reproduction is the ultimate priority [29]. Reproductive health is proportionately tied to healthspan and lifespan [109].

7.3. Sex and Gender Differences in Reproduction and Longevity

In humans, reproduction’s tie to longevity shows sex-specific patterns, reinforcing its role as a health marker [8]. Women outlive men by 5–10% globally, a gap tied to reproductive biology [8]. Female longevity correlates with later menopause and childbirth, suggesting sustained reproductive capacity buffers against HLFD [109]. Men’s reproductive peak (20s–30s) aligns with peak physical health, but testosterone decline after 40 parallels systemic wear (muscle loss, immune weakening, and cognitive fade) [71]. Social factors amplify this: men historically faced higher mortality from risk-taking or violence, while women’s reproductive role favored survival [8]. Loneliness, reducing physical activity, accelerates decline in both sexes but hits men harder due to weaker social networks post-reproduction [59]. These differences highlight reproduction’s systemic anchor; its fade signals HLFD onset [22].

7.4. Cellular Drive: Reproduction at the Core

Zoom in to the cellular level, and it’s still about reproduction. Every cell comes from division, mitosis for growth, meiosis for gametes [6]. In complex organisms, body cells (somatic) keep the organism alive so germ cells (reproductive) can do their job [18]. Even in mules, where gamete production fails, the cellular intent is there [113]. In bacteria, it’s even clearer: they split via binary fission, their whole existence geared toward replicating DNA [128]. Survival traits, like resisting antibiotics, help them reproduce more [28]. Life’s smallest units scream reproduction as their purpose [29].

7.5. Asexual Organisms: Reproduction Without Mates

Asexual reproducers like bacteria or certain plants (think strawberry runners) double down on this. Their survival adaptations, such as a plant’s drought resistance, exist to ensure they can keep splitting or sprouting clones [11]. Reproduction is biological life’s singular purpose [29]. Mules’ instincts, though fruitless, reveal reproduction’s hardwired dominance [113]. Health decline acts as a gatekeeper, ensuring only the strong reproduce [56]. From cells to societies, every function orbits reproduction, either directly or through relatives [141]. Life’s design, down to its core, is about making more life [29]. A properly regulated biological system, even at older ages, functions at a “youthful” capacity [112]. Dysfunction, not time, dictates systemic failure [44]. In most species, including humans and other mammals, fertility generally decreases when there is dysregulation in energy metabolism (due to mitochondrial damage or shortage of nutrition) [34]. Paradoxically, not unlike Earth’s gravitational driver, dysregulation is driven by reduced reproductive health. The reproductive-longevity axis seems clear. We propose that dysregulated fertility is also a leading biomarker for the onset of HLFD [22].

7.6. Humans Were Programmed to Reproduce Until Death

Historically, humans reproduced across their lifespan, with no evolutionary “off switch” [109]. Pre-industrial data show women bore children into their 40s, and men fathered offspring until death, often past 60 [109]. Grandparental care boosted offspring survival, extending reproductive impact indirectly [109]. Modern longevity outpaces this design; post-reproductive years now stretch decades, but HLFD kicks in when reproductive regulation falters [22]. Social isolation in later life, reducing activity, mirrors this decline [59]. Our biology was not built for a long post-reproductive phase; sustained reproduction, or its proxies (e.g., progesterone, testosterone, estrogen, Klotho, etc.), could theoretically align lifespan with healthspan, dodging HLFD’s grip [81]. Hormone replacement therapy (HRT) already increases post-peak reproductive capacity health, albeit incompletely. We suggest adding Klotho to the key regulators we aim to maintain in balance.

8. Species Demonstrating Reproduction Tied to Longevity

To further illustrate that life is programmed to live and reproduce, we present examples across species where longevity aligns with sustained reproductive capacity, defying any programmed decline [40]. These cases reinforce that systemic regulation dictates vitality [75], with Klotho potentially mirroring these natural mechanisms in humans [82].

8.1. Animals: Longevity and Reproduction Patterns

Long-lived animals keep reproducing well into old age; their longevity often aligns with reproductive strategies that prioritize survival and genetic propagation, not a programmed decline [40].

• Bowhead Whale (Balaena mysticetus):

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  Lifespan: Over 200 years [46].

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  Reproduction: Do not reach sexual maturity until around 25 years and can reproduce into their later decades, with calving intervals of 3–4 years. Evidence suggests females remain fertile for much of their lives. A 90-year-old female was found pregnant, and males show active spermatogenesis late in life [47].

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  Tie to Longevity: Sustain reproductive capacity over centuries [72]. No menopause-like shutdown, just a steady reproductive hum [47].

• Galápagos Tortoise (Chelonoidis nigra):

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  Lifespan: Up to 170+ years [21].

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  Reproduction: Females lay eggs (2–16 per clutch) annually or biennially from age 20–25 onward, with no clear reproductive cutoff. Males remain fertile too [21].

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  Tie to Longevity: Reproduction does not stop; it is lifelong [40].

• Ocean Quahog (Arctica islandica):

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  Lifespan: Over 500 years [19].

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  Reproduction: These clams are gonochoristic (separate sexes) and spawn annually after reaching maturity around 6–10 years. They release millions of gametes into the water, with no evidence of reproductive senescence. Samples from 200-year-olds show viable sperm and eggs [19].

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  Tie to Longevity: Constant reproduction over centuries [19].

• Naked Mole Rat (Heterocephalus glaber):

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  Lifespan: Up to 37 years [17].

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  Reproduction: Queens in their eusocial colonies breed continuously, producing litters of 10–20 pups every 80–90 days well into their 30s. Subordinates do not reproduce, but queens show no fertility drop-off [17].

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  Tie to Longevity: Cancer resistance (via hyaluronan) and stable proteasomes keep them reproductively active [133].

• Greenland Shark (Somniosus microcephalus):

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  Lifespan: Estimated 272–512 years, based on radiocarbon dating of eye lenses [103].

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  Reproduction: Sexual maturity hits late, around 150 years, and they are ovoviviparous, birthing live pups (10–20 per litter). Old females (300+ years) show ovarian activity, suggesting reproduction persists [103].

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  Tie to Longevity: No reproductive shutdown [40].

The longest-lived animals often keep reproducing, albeit at a leisurely pace, with no programmed “aging” halt [40]. Their longevity seems tied to repair and environmental stability, not a fertility cliff [75].

8.2. Plants: Trees and Clonal Colonies: Reproduction over Millennia

Trees, especially the oldest ones, support this hypothesis. Many live thousands of years and keep reproducing, often via seeds or clonal growth, defying any aging script [40].

• Great Basin Bristlecone Pine (Pinus longaeva):

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  Lifespan: Up to 4,856 years (Methuselah) or more, possibly 5,000+ for some [85].

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  Reproduction: These pines produce cones annually after maturity (50–100 years), with viable seeds even in their oldest specimens. Growth slows, but cone production persists; 3,000-year-olds still seed the landscape [85].

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  Tie to Longevity: Constant reproduction over millennia, “programmed to live,” no senescence, just persistence [121].

• Pando (Populus tremuloides):

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  Lifespan: Estimated 14,000–16,000 years as a clonal colony; individual stems live ~130 years [32].

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  Reproduction: This quaking aspen colony in Utah spreads via root suckers, sprouting new stems constantly. Sexual reproduction (seeds) is rare due to climate shifts, but clonal growth is relentless, with 80,000 years of potential if dated to its genetic origin [32].

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  Tie to Longevity: Root system immortality and stem turnover dodge aging [52]. It is a living factory of life [121].

• Old Tjikko (Picea abies):

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  Lifespan: 9,550 years via clonal roots; above-ground trunks cycle every ~600 years [79].

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  Reproduction: This Norway spruce in Sweden clones itself via layering (roots sprout new trunks) and occasionally produces cones with viable seeds [79]. It has been bringing forth life since the Ice Age [79].

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  Tie to Longevity: Clonal strategy bypasses individual trunk death; life’s program keeps running [121]. Seed production, though less frequent, shows reproductive capacity endures [79].

• Llangernyw Yew (Taxus baccata):

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  Lifespan: 4,000–5,000 years for this Welsh tree [132].

  ◦

  Reproduction: Yews are dioecious; females produce berries (arils) with seeds annually into extreme age. Pollen from males remains viable too; 4,000-year-olds still contribute [132].

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  Tie to Longevity: Lifelong seed output; reproduction drives vitality; life never quits [40].

• General Sherman (Sequoiadendron giganteum):

  ◦

  Lifespan: ~3,200 years for this giant sequoia [127].

  ◦

  Reproduction: Produces thousands of cones yearly, with seeds viable in its third millennium. Cone production ramps up with age as the tree grows larger [127].

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  Tie to Longevity: Modular growth sustains function [127].

Long-lived trees do not stop reproducing; they adapt, whether through seeds or clones [40]. Their longevity ties to environmental resilience, modular design, and reproductive capacity [85].

8.3. Other Organisms: Corals, Sponges, and Beyond

Beyond animals and trees, some of the oldest living things reinforce this thesis [40].

• Black Coral (Leiopathes spp.):

  ◦

  Lifespan: Up to 4,270 years (Hawaii specimen) [115].

  ◦

  Reproduction: These deep-sea corals release gametes annually or biennially, with colonies growing and spawning for millennia. No reproductive senescence observed [115].

  ◦

  Tie to Longevity: Constant reproduction mirrors life’s persistence [121].

• Glass Sponge (Hexactinellida):

  ◦

  Lifespan: Over 2,300 years (Caribbean barrel sponges); some Pacific species may hit 10,000+ [30].

  ◦

  Reproduction: Asexual budding and sexual gamete release persist throughout life. Old specimens remain reproductively active [30].

  ◦

  Tie to Longevity: Lifelong reproduction; life keeps making more life [121].

• Hydra (Hydra spp.):

  ◦

  Lifespan: Potentially immortal; lab studies show no senescence over decades [96].

  ◦

  Reproduction: Asexual budding every few days; sexual reproduction under stress. Both continue indefinitely [96].

  ◦

  Tie to Longevity: Stem cell renewal and telomerase activity dodge aging entirely [96]. It is the ultimate “programmed to live and create more life” case [121].

8.4. Synthesis: Reproduction and Longevity Tied?

Do Longest-Lived Species Keep Reproducing Longer? Yes.

Long-lived species sustain reproduction lifelong, often at a slow, steady pace, and the decline signals dysregulation and decline [47,19]. Exceptions like naked mole rat queens (continuous) [17] and Hydra (endless) [96] amplify this. Some (e.g., Greenland sharks) exhibit no “hard stop” [103]. Reproduction drives longevity across kingdoms. Bowheads breed at 90+ [47], quahogs spawn at 200 [19]. Even “programmed death” species like Pacific salmon [12] and female octopi [7] reflect this: In Pacific salmon, hormonal changes triggered by spawning lead to rapid senescence, or aging, resulting in death. In octopi, post-spawn cortisol or optic gland signals crash their systems, but optic gland removal extends octopus lifespan post-partum [143]. HLFD may govern these too.

Klotho sustains reproductive health in mice [80] and humans [22]. Could Klotho analogs tweak these triggers, extending life beyond reproductive peaks? [81] These examples across kingdoms demonstrate that life’s program is to perpetuate itself, not to age, with longevity tied to reproductive continuity and systemic resilience, mirroring the role Klotho supplementation could play in preventing HLFD in humans.

9. Klotho: The Master Regulator and Optimal Balance for Longevity

Klotho is the linchpin of systemic regulation [81]. Klotho is not just an anti-aging protein. We put forth that it is the primary regulator of systemic balance, which yields us the gift of healthy life function, “youth” [82].

9.1. Klotho’s Role in Metabolism

Klotho directly influences glucose and phosphate metabolism, insulin signaling, and mitochondrial efficiency [81]. Studies have shown that low Klotho levels correlate with metabolic diseases such as type 2 diabetes, arteriosclerosis, and obesity [147].

9.2. Klotho and Autophagy: Facilitating Cellular Clearance

Autophagy is a critical process for degrading and recycling cellular components, ensuring cellular health and function [157]. Klotho has been shown to influence autophagy through the modulation of key signaling pathways:

• AMPK Activation: Klotho upregulates AMP-activated protein kinase (AMPK), promoting autophagy [158].
• mTORC1 Inhibition: Klotho inhibits mTORC1, preventing suppression of autophagy [159].

9.3. Klotho and Mitochondrial Biogenesis: Sustaining Metabolic Activity

Mitochondria are essential for energy production, and their dysfunction can lead to decreased metabolic activity [160]. Klotho supports mitochondrial health through several mechanisms:

• PGC-1α Activation: Klotho enhances PGC-1α, promoting mitochondrial biogenesis [161].
• SIRT1 Interaction: Klotho indirectly stimulates SIRT1, improving mitochondrial function [162].

9.4. Klotho and the Immune System

Klotho also functions as an immune modulator, regulating inflammation and oxidative stress responses [95]. Dysregulation of Klotho is associated with chronic inflammatory diseases, autoimmune dysfunction, and impaired immune surveillance [81].

9.5. Klotho and Immune Function: Enhancing Cellular Clearance

The immune system plays a vital role in identifying and removing senescent or damaged cells [163]. Klotho influences immune function in the following ways:

• Macrophage Regulation: Klotho modulates macrophages, promoting efficient phagocytosis [164].
• Inflammation Modulation: Klotho inhibits NF-κB signaling, reducing chronic inflammation [165].

9.6. Klotho as a Key to HLFD Treatment

Given its central role in metabolism, immunity, and cellular maintenance, Klotho should not be seen merely as a longevity factor but as a primary therapeutic target for treating HLFD [81]. We put forth that mRNA Klotho therapy may offer a way to restore physiological equilibrium, rather than artificially delaying symptoms of biological decline [65].

9.7. Klotho’s Role in Longevity-Focused Research and Pathways

Klotho seems to be upstream of several key biological processes, including telomere shortening, mitochondrial health, sirtuins, and indirectly, NAD+ levels [81]. Klotho likely influences these processes, helping regulate how cells age and function [81].

• Telomere Shortening as a Function of Dysregulation: Research suggests telomere shortening is a function of cellular dysregulation, driven by factors like oxidative stress and psychological stress, which exacerbate telomere attrition [35]. For instance, telomeres shorten in response to biochemical stressors (e.g., oxidative stress) and psychological stressors in a dose-response manner, as seen in high-stress caregivers [35]. Reduced Klotho levels contribute to telomere shortening [38]. Klotho plays a significant role in maintaining telomerase activity, the enzyme that extends telomeres [38]. Studies show that lower Klotho levels reduce telomerase activity, leading to shorter telomeres [92]. In cancer cells, Klotho suppresses TERT expression, reducing telomerase activity, as seen in colorectal, ovarian, and gastric cancer cells [88,107,146].
• Mitochondrial Health: Klotho is crucial for mitochondrial health, regulating oxidative stress and mitochondrial function, particularly in kidney disease [119]. Studies show Klotho modulates signaling pathways involving manganese-containing superoxide dismutase (Mn-SOD) and transcription factors FoxO and Nrf2, known antioxidant systems, and other mitochondrial function regulators like mitochondrial uncoupling protein 1 (UCP1), B-cell lymphoma-2 (BCL-2), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) [147]. In aged muscle progenitor cells, decreased α-Klotho levels were associated with vacuolated mitochondria and compromised cristae structure, which SS-31 treatment reversed, supporting Klotho’s role in mitochondrial energetics [118]. Klotho’s involvement in mitochondrial biogenesis is also noted in skeletal muscle function, highlighting its broader impact [9].
• Sirtuins: The evidence suggests that Klotho interacts with sirtuins, particularly SIRT1, a NAD+-dependent deacetylase involved in healthy regulation [45]. Studies show that Klotho deficiency downregulates SIRT1 expression and activity in aortic endothelial and smooth muscle cells, and activating SIRT1 with SRT1720 abolishes Klotho deficiency-induced arterial stiffness and hypertension in mice [45]. Exercise training has been shown to improve heart function in rats by activating both sirtuins (SIRT1, SIRT3) and Klotho, suggesting a synergistic relationship [54]. Reviews also highlight sirtuins and Klotho’s shared anti-oxidative and anti-inflammatory roles in sleep-related cardiovascular diseases [138]. Klotho supports SIRT6 indirectly via stress reduction, suggesting it is a vital teammate in DNA repair [101].
• NAD+ Levels: Klotho likely affects NAD+ indirectly through sirtuins, as sirtuins need NAD+ to function [66]. Studies show restoring NAD+ can protect aged cells, and since Klotho influences sirtuins, it may play a role in maintaining NAD+ levels [118]. Klotho may regulate NAD+ metabolism and influence its availability through its effects on oxidative stress, mitochondrial function, and sirtuin activation [67]. This suggests a synergistic relationship where Klotho indirectly enhances NAD+ function, leading to better cellular repair, longevity, and energy production [68]. There is also evidence showing that NAD+ may upregulate Klotho, primarily through pathways involving sirtuins (SIRT1), oxidative stress reduction, and mitochondrial function [45]. NAD+ is essential for SIRT1 activation, and SIRT1 has been linked to increased Klotho expression [89]. Studies suggest that SIRT1 activation can enhance renal and vascular Klotho levels, potentially extending lifespan and improving metabolic health [64]. The implication is that at least some of the benefits from NAD+ may be tied to Klotho upregulation.
• Stem Cells: Klotho’s impact on telomerase is strongest in stem cells, where it helps maintain their ability to divide and regenerate, potentially offering new ways to treat “aging” related diseases [92]. Studies in stem cells, like adipose-derived stem cells (ADSC), show that Klotho deficiency accelerates aging by impairing telomerase activity, leading to shorter telomeres and reduced proliferation [37]. Klotho deficiency diminished telomerase activity by altering TERF1 and TERT expression, causing impaired differentiation and senescence [37].
• Autophagy: Autophagy maintains cellular homeostasis and is linked to aging processes; its regulation supports Klotho’s role in cellular maintenance [39].

9.8. Klotho: Driver of HLFD

Klotho’s absence in mice triggers rapid HLFD-like decline, osteoporosis, infertility, frailty [80], while supplementation reverses vascular calcification [65], cognitive decline [33], and infertility [80] in mice and primates. In humans, low Klotho (below 600 pg/mL) predicts mortality [23], and higher levels in centenarians hint at protection [69]. This suggests Klotho drives systemic balance, not just reflects it.

10. Klotho and Reproductive Health, Both Biomarkers for HLFD

10.1. Klotho and Reproduction

Klotho is not only a master regulator of metabolism and immunity but also holds a critical axis with our reproductive hormones [22]. Its levels are directly correlated with ovarian reserve, sperm motility, and reproductive lifespan [22]. Women with higher circulating Klotho levels maintain longer fertility windows [131], while men with sufficient Klotho expression exhibit higher testosterone levels and improved spermatogenesis [71]. Klotho is central to reproductive health, regulating estrogen, progesterone, testosterone, and other reproductive hormones [14]. Its decline accelerates the onset of both reproductive health decline and broader systemic dysfunction. We hypothesize that Klotho’s regulation of hormonal pathways (e.g., via FGF23 and insulin signaling) underpins these effects [81].

10.2. Klotho in Pregnancy and Fetal Development

Klotho levels are highest in fetuses during early development, where it plays a crucial role in supporting rapid metabolic and cellular growth [104]. Pregnant women also experience increased Klotho levels, which help maintain maternal health and ensure proper fetal development [27]. This makes Klotho essential in the early life stages, and its decline in later years accelerates the dysregulation associated with HLFD [81]. Klotho seems to work as the body’s firefighting force. Its surge in response to stressors like exercise shows it supports life’s systems, not an aging fight [9]. It bolsters telomerase (telomere length) [38], synergizes with SIRT6 (repair) [101], preserves NAD+ (mitochondrial energy) [66], and sustains stem cells (regeneration) [92].

11. Klotho Levels During the Different Stages of Life and Systemic Regulation

Life progresses through stages of functional optimization, dictated by regulatory control rather than time [40]:

• Fetal Development: Klotho expression is highest, ensuring rapid cellular differentiation, cellular genesis, and repair [104].
• Infancy and Childhood (0–12 years): Elevated Klotho levels maintain immune resilience, cognitive growth, and systemic function [104].
• Adolescence (13–18 years): Klotho reaches peak levels, ensuring peak metabolic function, reproductive health, and systemic balance [23].
• Young Adulthood (18–35 years): Klotho levels plateau into a healthy sustainable state that keeps the system functioning properly through reproductive and child-rearing years [23].
• Midlife (35+ years): When systemic dysregulation occurs, Klotho declines, leading to HLFD and progressive functional failure [81].
• Advanced Age: In well-regulated individuals (e.g., centenarians), Klotho remains higher, better combating HLFD and maintaining function despite chronological aging [69].

These stages further support that aging is not inevitable; rather, it is an effect of systemic regulation failure [40]. Rather than reversing time, our goal should be to stabilize Klotho at its natural plateau, the period of peak health between 18 and 35 years, emphasizing the need for precise regulation rather than indiscriminate intervention [81].

12. The Stressor Paradox: Klotho’s Role

Stressors like caloric restriction (CR) [149], exercise [9], and even smoking [100] spark repair via Klotho upregulation. CR boosts Klotho in rats [149], exercise triggers Klotho-driven recovery in humans [9], and early oxidative stress triggers it briefly [100]. However, excess, overtraining [110], chronic smoking [137], or starvation overwhelm the system, tipping into HLFD [81]. Life thrives on controlled stress; Klotho is the fulcrum [81]. mRNA therapy could sustain this balance directly, bypassing excessive and uncontrolled stressor risks [65]. Ramakrishnan also critiques interventions like rapamycin for side effects like immunosuppression, echoing our view that such approaches disrupt rather than restore balance, unlike mRNA Klotho therapy [157, 70].

Table 3. Biomarkers and HLFD Indicators, Proposed Options.

Biomarker	HLFD Indicator	Reference
Klotho Levels	Plasma Klotho levels below 600 pg/mL indicate early HLFD risk; contrast with optimal 1400–2000 pg/mL	[23]
Testosterone	Levels below reproductive equilibrium, correlated with systemic failure	[71]
Estrogen	Premature ovarian failure or disrupted menstrual cycle	[131]
Vitamin D Metabolism	Dysregulated synthesis & utilization, indicating metabolic instability	[63]
Glucose-Insulin Regulation	Insulin resistance and increased risk of diabetes	[147]
Inflammatory Markers	Chronic elevation of IL-6 and TNF-α, indicative of immune dysfunction	[44]
Neurological Function	Cognitive decline, hippocampal shrinkage, and impaired neuroplasticity	[33]

Table 3. Biomarkers and HLFD Indicators, Proposed Options.

Biomarker	HLFD Indicator	Reference
Klotho Levels	Plasma Klotho levels below 600 pg/mL indicate early HLFD risk; contrast with optimal 1400–2000 pg/mL	[23]
Testosterone	Levels below reproductive equilibrium, correlated with systemic failure	[71]
Estrogen	Premature ovarian failure or disrupted menstrual cycle	[131]
Vitamin D Metabolism	Dysregulated synthesis & utilization, indicating metabolic instability	[63]
Glucose-Insulin Regulation	Insulin resistance and increased risk of diabetes	[147]
Inflammatory Markers	Chronic elevation of IL-6 and TNF-α, indicative of immune dysfunction	[44]
Neurological Function	Cognitive decline, hippocampal shrinkage, and impaired neuroplasticity	[33]

Table 4. Longevity Approaches, Flawed Assumptions, and HLFD Superiority.

Longevity Approach	Flawed Assumption	Why HLFD Is Superior	Reference
Caloric Restriction	Aging is metabolic wear & tear	HLFD shows an active metabolism drives repair, not just energy intake	[149]
Senolytics	Aging is "zombie" cells	HLFD demonstrates healthy cellular turnover maintains senescent function and clearance	[74]
Rapamycin & mTOR Inhibition	Aging is hyperactive growth	HLFD calls for restoring a healthy balance, not just slowing decline	[70]

Table 4. Longevity Approaches, Flawed Assumptions, and HLFD Superiority.

Longevity Approach	Flawed Assumption	Why HLFD Is Superior	Reference
Caloric Restriction	Aging is metabolic wear & tear	HLFD shows an active metabolism drives repair, not just energy intake	[149]
Senolytics	Aging is "zombie" cells	HLFD demonstrates healthy cellular turnover maintains senescent function and clearance	[74]
Rapamycin & mTOR Inhibition	Aging is hyperactive growth	HLFD calls for restoring a healthy balance, not just slowing decline	[70]

Unlike these approaches, targeting the support of healthy life function programming offers a fundamentally different strategy, restoring the body’s natural regulatory equilibrium rather than trying to artificially delay symptoms [67]. Stressors like CR [149], HIIT [9], saunas [86], fasting [97], and exercise [9], for example, are not healthy on their own; they all trigger protective and repair mechanisms, such as Klotho’s overproduction response to regulate, maintain, and strengthen healthy life function [81].

13. Clinical Implications

By using reproductive biomarkers in early HLFD diagnosis, clinicians can detect and intervene before full systemic failure occurs [22]. mRNA Klotho therapy may present the first viable intervention to restore reproductive health and systemic function simultaneously [65], aligning with the broader goal of maintaining life function rather than attempting to reverse aging [81]. Klotho’s support for telomerase [38], SIRT6 [101], NAD+ [66], and stem cells [92] makes it the clinical key; life endures longer with repair thriving in support of reproductive function.

14. HLFD as a Medical Diagnosis: Biomarkers and Diagnostic Tools

To be recognized as a disease, HLFD should be measurable through objective biomarkers and diagnostic tests [44].

Potential Diagnostic Tools for HLFD

• Blood Tests for Klotho Levels: Plasma levels below 600 pg/mL correlate with early HLFD symptoms; ELISA protocols established in Cheema et al. (2022) could standardize this threshold [23].
• Comprehensive Hormone Panels: Assess testosterone, estrogen, and progesterone function to detect dysregulation [14].
• Metabolic Assays: Evaluate glucose regulation and vitamin D metabolism for systemic health markers [147,63].
• Inflammation Markers: Chronic immune activation (e.g., IL-6, TNF-α) suggests systemic dysregulation [44].
• Cognitive Function Tests: MRI scans showing hippocampal shrinkage may indicate HLFD-linked cognitive decline [33].

By defining HLFD as a measurable disease, we transition from treating “aging” to targeting the true pathology: systemic dysregulation [80]. Restoring Klotho homeostasis could serve as the first comprehensive treatment for HLFD [65]. We propose a pilot study to validate these biomarkers, using ELISA for Klotho and correlating levels with health outcomes in a cohort of volunteers to be treated with mRNA Klotho supplementation.

15. Finding the Optimal Balance for Longevity and Healthspan

The goal should be to restore Klotho levels to the optimal plateau seen in early healthy adulthood, where all systems function at their best without triggering unwanted metabolic imbalances [81]. Maintaining balance in Klotho levels is crucial to avoid the potential detrimental effects of overproduction [23].

15.1. Why Over-Restoration May Be a Mistake

Efforts like the research into the Yamanaka factor reprogramming seek to revert cells to an early developmental stage, ignoring the risks of excessive re-stimulation, including loss of cellular identity, cancer risk, and metabolic disruption [130,1]. Several strategies have been proposed to extend longevity and healthspan, including caloric restriction [97], senolytics [74], rapamycin [70], and metformin [13], to name a few. These approaches attempt to slow down biological decline [43]. However, each of these approaches fails to restore true biological function and may cause undesirable side effects [70]. They do not restore healthy system function, “youth,” at the systemic level [112]. We propose that mRNA Klotho therapy, on the other hand, is one approach that could restore endogenous Klotho production, avoiding negative feedback suppression, as has been seen with exogenous supplementation of key hormones [14], and maintaining natural homeostasis [65]. This makes mRNA Klotho therapy, in our assessment, the most promising approach for HLFD prevention and reversal [81]. We put forth that mRNA Klotho supplementation therapy could maintain Klotho within the optimal physiological range, allowing the body to regulate itself naturally without forcing unnatural reversions to early developmental states or unnatural cessation of healthy function, such as mTOR function or nutrient and mineral metabolism [70,63].

15.2. What Is the Optimal Level of Klotho for Supercharged Health and Lifespan?

Serum Klotho was measured by ELISA in 10,069 individuals aged 40–79 years in the United States [23]. Further analysis of the study reveals the optimal Klotho serum level lies between 1400 and 2000 pg/mL [23]. The vast majority of the population is outside of this optimal range [23]. Low serum Klotho is associated with all-cause mortality among a nationally representative sample of American adults [23]. mRNA Klotho supplementation therapy could shift the whole population into the healthier zone, a hypothesis we propose testing through clinical trials [65]. If DNA repair persists and Klotho’s support outpaces entropy’s wear, it seems we could significantly extend lifespan/healthspan? [8,121].

16. Why mRNA Klotho Therapy

16.1. mRNA vs. Recombinant Protein Therapy

mRNA therapy enables endogenous production of Klotho, ensuring sustained physiological regulation [117], whereas recombinant protein therapy requires frequent injections, suffers from instability, and has limited bioavailability [87]. This intervention may inevitably lead to negative feedback regulation atrophying the biological system’s ability to produce the very molecules it is trying to rescue [14].

16.2. mRNA vs. Gene Therapy

Gene therapy involves permanent genetic modification, which carries risks of uncontrolled gene expression, off-target effects, and immune reactions [55], whereas mRNA is transient, allowing precise dosing and reducing long-term risks [117].

16.3. mRNA Therapy Allows Natural Feedback Regulation

Unlike external Klotho protein supplementation, mRNA-based therapy maintains natural homeostasis, preventing excessive Klotho levels that could disrupt metabolic balance [23,117].

17. For Discussion: HLFD as a Treatable Disease

HLFD should be recognized as the true driver of biological decline. Aging does not exist as a distinct process; it is merely the consequence of systemic dysregulation and loss of homeostasis [44]. Life is an active, energy-intensive, and combustive process [84], and when its regulatory mechanisms fail, decline occurs [94]. By restoring optimal function, we can halt the progression of HLFD, extend healthspan, and reframe biological decline as a treatable disorder rather than an inevitability [81]. We invite the medical community to embrace HLFD as a diagnosable and treatable syndrome [44]. DNA’s immortality tells us that no aging program exists [148]. Klotho’s firefighting against stressors or entropy shows that the causes of HLFD can be treated and reversed. It is time to reproductive health indicates that life is created to persist [81]. By supporting healthy life function and maintaining the system at the appropriate levels, could we extend life to 200? 300? Years beyond? Could we echo nature’s longest-lived species? We suggest this is possible.

18. Scientific Implications: New Direction, Better Approaches

HLFD reframes aging as a treatable disease, shifting research from slowing “aging” to sustaining life’s inherent programming. Evidence from Deinococcus radiodurans (indefinite DNA repair) [148] and Picea abies (9,550 years of cloning) [79] suggests life persists unless dysregulated [121]. Could Klotho supplementation and reproductive health support replicate this in humans? Aim to maintain cellular turnover, repair, and reproductive function as in bowheads and sequoias and other long-lived species [47,127]. Ramakrishnan’s molecular insights into ribosome dysfunction suggest a need to explore Klotho’s role in protein homeostasis, potentially upstream of sirtuins and NAD+ [157; 80, 66].

18.1. Potential Future Research

• Klotho’s Primacy: Investigate Klotho’s upstream role vs. sirtuins, NAD+, or mTOR. Is it the dominant regulator, as knockout mice suggest? [80,66,70]
• Stressors’ Mechanism: Test if benefits from CR, HIIT, or fasting stem primarily from Klotho surges. Could we bypass excessive stressor damage (e.g., compare Klotho therapy vs. fasting in mice) [149,9,97].
• Reproductive Link: Quantify Klotho’s impact on fertility windows (e.g., ovarian reserve, testosterone) across species and humans [22,131,71].
• Genetic Conditions: Explore Klotho-WRN interactions in Werner Syndrome and phosphate metabolism in progeria to confirm HLFD’s scope [106,51,65]; similarly, assess Klotho’s potential in Bloom Syndrome [141,142] and Cockayne Syndrome [154,155].
• The Final Frontier: Explore microgravity and zero gravity’s effects on Klotho. Could Klotho supplementation support space exploration?

18.2. Proposed Studies

• Cohort Study: Measure Klotho via ELISA in 500 adults (35–65), correlating levels (600 vs. 1400–2000 pg/mL) with HLFD biomarkers (e.g., fertility, inflammation) [23].
• Mouse Trial: mRNA Klotho therapy to sustain the mouse correlate of 1400–2000 pg/mL in humans, assessing lifespan, reproduction, and systemic health vs. controls [65].
• Stress Test: Compare Klotho therapy alone vs. stressor-induced Klotho spikes (e.g., fasting) in animal models, measuring repair efficiency and side effects [149,97].

18.3. Potential Impact

• Lifespan Extension: Sustaining Klotho at 1400–2000 pg/mL could push human lifespan beyond its accepted limit; if repair outpaces entropy, could we optimize lifespan in the global population to mirror and surpass centenarians? [8].
• Healthspan Gains: Restoring Klotho could reverse HLFD symptoms, metabolic disease, infertility, neurodegeneration, mirroring long-lived species’ and long-lived humans’ resilience [147,22,33].
• Societal Shift: A population with optimal Klotho could reduce mortality and healthcare burdens, reducing healthcare costs and redefining human potential [23].

18.4. Challenges and Considerations to Be Studied

• Mechanistic Clarity: Does Klotho dominate other pathways? Its synergy with NAD+ and sirtuins needs mapping to better understand these relationships [66,45].
• Therapy Safety: Overproduction risks (e.g., metabolic imbalance) must be studied; mRNA’s transient nature may mitigate this vs. gene therapy [23,117,55].
• Feasibility: Scaling mRNA therapy requires cost and delivery breakthroughs; can it match nature’s showcased longevity (e.g., quahogs, pines)? [19,85,117].

18.5. Broader Questions

• Could Klotho and other therapies that correctly target HLFD mimic Hydra’s immortality in humans, maintaining cellular function and health? [96]
• If reproduction drives longevity, can Klotho and other HLFD therapies extend fertility exponentially, as in queen bees, naked mole rats, or tortoises? [142,21]
• Are stressors obsolete if Klotho therapy delivers repair without damage? Or are controlled stressors key to driving healthy function, as evidenced by gravity? [81,65]

Appendix

Reference List (157 Entries).