The Optimal Treatments for Type 2 Diabetes from The Perspective of Anti-Aging Medicine

1. Introduction

Aging is a complex biological process that involves a gradual decline in the human body's structure and function and increases the risks of various aging-related diseases, including neurodegenerative diseases such as Alzheimer's disease (AD), cardiovascular diseases (CVD), metabolic diseases such as type 2 diabetes, musculoskeletal diseases, and immune system diseases [1]. Recent studies have identified several key hallmarks, or characteristics, of aging at the molecular, cellular, and systemic levels [2,3]. These include oxidative stress [4], inflammation [5], advanced glycation end products (AGEs) [6], dysbiosis [7,8], DNA damage [9,10], telomere shortening [11], epigenetic alterations [12,13], loss of protein balance [14], deregulated nutrient-sensing [15], altered intercellular communication [16,17], mitochondrial dysfunction [18,19], loss of nicotinamide adenine dinucleotide (NAD+) levels [20,21], cellular senescence [22], and stem cell exhaustion [23,24], impaired macro-autophagy [25,26], and hormonal changes [27,28].

Current research on aging focuses on elucidating how various endogenous and exogenous stresses participate in the regulation of aging [1]. Furthermore, thorough research on the pathogenesis of aging to identify clinical treatment methods for aging-related diseases could decrease the incidence and development of aging-related diseases and, in turn, promote healthy aging and longevity [1]. Here, we will report the influence of type 2 diabetes on the clinical manifestations of aging and hallmarks of aging.

A protein complex called AMP-activated protein kinase (AMPK) regulates energy balance within cells and controls cellular metabolism. AMPK signaling declines with aging, enhancing the aging process [29]. AMPK activity is reduced in type 2 diabetes [30]. Therefore, numerous studies have highlighted the remarkable potential of AMPK and its activators in treating type 2 diabetes. The mammalian target of rapamycin complex 1 (mTORC1) is a key component of cellular metabolism that integrates nutrient sensing with cellular processes that fuel cell growth and proliferation, and inhibition of mTORC1 with therapeutic rapamycin promotes health and longevity in diverse model organisms [31]. Hyperactive mTORC1 has been proposed to offer a novel perspective for type 2 diabetes in terms of pathogenesis, clinical focus, and treatment strategy [32].

We will consider effects of AMPK activation and mTORC1 inhibition on hallmarks of aging and the development and progression of type 2 diabetes and its complications. Furthermore, we searched the influence of nutritional interventions and drugs that improve aging hallmarks by AMPK activation and mTORC1 inhibition on type 2 diabetes and its complications. We would like to propose optimal treatments for type 2 diabetes from the perspective of anti-aging medicine.

2. The Influence of Type 2 Diabetes on the Clinical Manifestations of Aging

The clinical manifestations of aging are shown in Figure 1.

2.1. Hair Aging

Dysregulation in the balance of the melanocyte spectrum within the hair follicle is the underlying cause of physiological and pathological grey hair [33]. During the progressive deterioration of cellular functions with aging, melanin synthesis is impeded after tyrosinase activity is reduced [34]. Type 2 diabetes is usually accompanied by premature grey hair [35].

2.2. Skin Aging

Diabetes causes increased production of AGEs, which may lead to irreversible damage to collagen fibers and early and more accentuated signs of skin aging [36]. In fact, higher trans-epidermal water loss was observed in patients with diabetes, who also showed lower skin elasticity and wrinkles with greater volume, area, and depth [36]. In addition, patients with diabetes presented polycyclic papillae and deformed and amorphous collagen fibers [36].

2.3. Voice Aging

Voice aging changes include a weak, breathy, or hoarse voice, and such changes are called presbyphonia. A scoping review including 188 published articles reported that laryngeal aging results in calcifications of the hyaline cartilages, decreased vocal folds lubrication, decreased neuromotor transmission, decreased hyaluronic acid, increased lamina propria stiffness, and changes in the thyroarytenoid muscles [37]. Concomitant aging of the respiratory system, hormonal changes, concomitant presbycusis, and medical comorbidities interact with the presbylarynx to induce presbyphonia [37].

Presbylarynx may be considered a sign of the health status of the elderly. It was found that patients with a higher probability of 10-year mortality exhibit more endoscopic signs of presbylarynx [38]. Type 2 diabetes is considered a risk factor for noticeable endoscopic signs of presbylarynx [38].

2.4. Ear Aging

Type 2 diabetes and sensorineural hearing loss are common health problems manifested with aging [39]. Individuals with diabetes have twice the incidence of hearing loss compared to those without diabetes, and those with prediabetes have a 30% higher rate of hearing loss [39]. Whether hearing loss is associated with diabetes independent of glycemic control remains to be determined.

2.5. Brain Aging

In the meta-analysis using the UK Biobank, compared to age, sex, education, and hypertension-matched healthy controls, patients with type 2 diabetes were associated with marked cognitive deficits, particularly in executive functioning and processing speed [40]. Type 2 diabetes was significantly associated with gray matter atrophy, primarily within the ventral striatum, cerebellum, and putamen [40]. The structural and functional changes associated with type 2 diabetes show marked overlap with the effects correlating with age but appear earlier.

2.6. Bone Aging

The meta-analysis revealed no significant difference in overall bone mineral density (BMD) between the nondiabetic and type 2 diabetic groups (mean difference [MD], -0.07; 95% confidence interval [CI], -0.17 to 0.03; P = 0.15) [41]. However, BMD at the lumbar vertebrae was significantly higher in nondiabetic individuals compared with those with type 2 diabetes (MD, -0.14; 95% CI, -0.22 to -0.06; P = 0.0009), as was the case with femoral neck BMD (MD, -0.11; 95% CI, -0.18 to -0.04; P = 0.002) [41]. Reduced BMD at the lumbar vertebrae and femoral neck can be a marker for bone aging in patients with type 2 diabetes.

2.7. Vascular Aging

Increased arterial stiffness has been shown to be predictive of CVD and all-cause mortality [42,43,44]. Arterial stiffening is known to increase with age, and arterial stiffening is especially accelerated in obese and diabetic females who tend to lose the normal protection afforded by female sex hormones against vascular disease and show an increase in CVD events relative to lean and non-diabetic premenopausal women [45,46,47]. The current standard for clinically assessing vascular stiffness is measurement of carotid-femoral pulse wave velocity (PWV) [48,49]. The meta-analysis showed that PWV was a useful noninvasive early marker for vascular dysfunction detection in patients with type 2 diabetes [50].

2.8. Muscular Aging

Insulin resistance has been closely associated with increased muscle protein degradation [51]. Accumulation of AGEs induces skeletal muscle atrophy and dysfunction, while oxidative stress and mitochondrial dysfunction caused by type 2 diabetes can lead to myocyte apoptosis. Therefore, patients with type 2 diabetes have a higher risk of developing sarcopenia, a progressive and generalized skeletal muscle disease linked to a higher risk of negative consequences such as falls, fractures, physical disability, and mortality [52]. Calf circumference was the most effective screening tool for sarcopenia in patients with type 2 diabetes [53].

2.9. Effect of Type 2 Diabetes on the Clinical Manifestations of Aging

Type 2 diabetes accelerates all clinical manifestations of aging.

3. The Hallmarks of Aging and Their Association with Type 2 Diabetes

3.1. Oxidative Stress

Oxidative stress, an imbalance between the production of reactive oxygen species (ROS) and the body's ability to neutralize them, is strongly linked to aging and age-related diseases [54]. Cumulative damage to mitochondria and mitochondrial DNA caused by ROS is one of the causes of aging [55]. Oxidative damage affects replication and transcription of mitochondrial DNA and results in a decline in mitochondrial function, which in turn leads to enhanced ROS production and further damage to mitochondrial DNA [55].

ROS are highly reactive and can damage cellular components, including DNA, proteins, and lipids, and such accumulated damage can impair cellular function and contribute to the aging process [56]. ROS can also cause mutations and breaks in DNA strands, leading to genomic instability. DNA damage can accumulate with age and is associated with an increased risk of age-related diseases [57]. Oxidative stress can trigger inflammation and accelerate the shortening of telomeres, which are associated with cellular aging and senescence [58].

Oxidative stress has been implicated in the progression of prediabetes to type 2 diabetes [59]. Oxidative stress contributes to insulin resistance, beta-cell dysfunction, and diabetic complications. Glutathione, a major antioxidant, is crucial for neutralizing ROS, but glutathione levels are notably low in type 2 diabetes, exacerbating oxidative stress and inflammation [60]. Elevated interleukin-6 (IL-6) levels further intensify inflammation and oxidative stress, disrupting insulin signaling and worsening complications such as nephropathy, retinopathy, and neuropathy. Type 2 diabetes is a chronic metabolic disease in which patients are prone to inflammation and oxidative stress [61,62], and hyperglycemia, hyperglycemia-induced oxidative stress, and inflammation are closely associated with the development and progression of type 2 diabetes and its complications.

3.2. Inflammation

Aging is associated with persistent activation of the immune system, witnessed by a high circulating level of inflammatory markers and activation of immune cells in the circulation and in tissue, a condition called "inflammaging [63]." Like aging, inflammaging is associated with increased risk of many age-related pathologies and disabilities, as well as frailty and death.

Low-grade inflammation represents a key driver of type 2 diabetes and CVD [64]. Inflammatory markers such as high-sensitive C-reactive protein (hs-CRP) and IL-6 predict the development of type 2 diabetes and its complications. Overnutrition, unhealthy diets, physical inactivity, obesity, and aging are all recognized triggers of inflammation, promoting insulin resistance and sustaining the pathogenesis of type 2 diabetes. The infiltration of proinflammatory cells in adipose tissue is associated with an increased production of key chemokines such as C-C motif chemokine ligand 2, proinflammatory cytokines including tumor necrosis factor α and IL-6 as well as reduced expression of the key insulin-sensitizing adipokine, adiponectin [65]. Adipose tissue inflammation is a key factor in the development of insulin resistance and type 2 diabetes in obesity.

In addition to adipose tissue, liver, muscle, and pancreas are the sites of inflammation in the presence of obesity [66]. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile [66]. These cells are crucial to produce pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce beta-cell dysfunction and subsequent insulin deficiency.

3.3. AGEs

AGEs arise from the nonenzymatic glycosylation of proteins and lipids [67]. Studies have demonstrated a clear correlation between AGE accumulation in tissues and blood glucose levels [68]. Accumulation of AGEs on nucleotides, lipids, and peptides/proteins is an inevitable component of the aging process in all eukaryotic organisms, including humans [69]. A substantial body of evidence shows that AGEs and their functionally compromised adducts are linked to changes seen during aging and the development of many age-related morbidities.

Even after correcting hyperglycemia, AGEs levels in diabetic tissues often fail to return to normal, leading to the concept of “metabolic memory” [70]. AGEs are not merely byproducts of hyperglycemia but are also implicated in the development of diabetes [71]. AGEs bind to the receptor for AGEs (RAGE), thereby activating proinflammatory signaling pathways [72]. AGEs bind RAGE, triggering multiple intracellular signaling pathways, including the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase that leads to increased production of ROS, thus contributing to generating a pro-oxidant environment [73]. These processes are also thought to contribute to the development of diabetic microvascular complications [74].

3.4. Dysbiosis

The gut microbiome plays a crucial role in modulating health and disease across the lifespan. As individuals age, the gut microbiome undergoes significant compositional and functional changes, often leading to dysbiosis—an imbalance associated with increased inflammation, weakened immunity, and metabolic disorders [75]. Inflammaging is closely linked to gut microbial alterations and contributes to neurodegenerative diseases, CV conditions, and metabolic disorders such as obesity and diabetes [75]. Additionally, the gut-brain axis is emerging as a critical pathway in neurocognitive aging.

A systematic review has reported a major gut microbiota alteration in obesity, characterized by a specific decrease in butyrate-producing bacteria and the production of metabolites and components that lead to metabolic impairments and affect the progression of various diseases associated with obesity through distinct signaling pathways, including insulin resistance, type 2 diabetes, and CVD [76]. Inflammation plays a major role as a link between gut microbiota dysbiosis and obesity-associated metabolic complications. Emerging evidence indicates that gut microbiota dysbiosis may contribute to the development of type 2 diabetes [77]. Individuals with type 2 diabetes exhibit notable changes in gut microbiota composition, including shifts in the balance between Firmicutes and Bacteroidetes, a reduction in butyrate-producing bacteria, and an increase in opportunistic pathogens [77]. Gut dysbiosis induces inflammation and consequently provokes both peripheral and cerebral insulin resistance and can amplify processes promoting AD. Additionally, the risk of increased progression of AD was revealed due to pre-diabetes, type 2 diabetes, and gut dysbiosis [78].

3.5. DNA Damage

Genomic instability is an important driver of aging. The accumulation of DNA damage contributes to aging by inducing cell death, senescence, and tissue dysfunction [9]. Inflammation is a hallmark of aging and the driver of multiple age-related diseases. DNA damage induces inflammation through activation of the cyclic GMP-AMP synthase-stimulator of interferon genes axis and nuclear factor-kappa B (NF-κB) activation [9]. Loss of efficient DNA damage repair can lead to accelerated aging phenotypes [10]. High levels of mutations in DNA repair mutants often lead to excessive cell death and stem cell exhaustion, which may promote premature aging [10]. Increasing DNA damage and mutation accumulation are the hallmarks of aging.

Cell senescence is defined as a state of irreversible cell cycle arrest combined with DNA damage and the induction of a senescence-associated secretory phenotype (SASP). This includes increased secretion of many inflammatory agents, proteases, and microRNAs, which have recently emerged as important regulators of cellular senescence and aging [79]. Recent evidence demonstrates that SASP may also play important roles in diabetes. White adipose tissue (WAT) cells are highly susceptible to becoming senescent both with aging but also with obesity and type 2 diabetes, independently of chronological age. WAT senescence is associated with hypertrophy of adipocytes, insulin resistance, and dyslipidemia [79]. Insulin resistance, high blood glucose levels, and increased body fat are linked to a chronically elevated inflammatory state [80]. This amplifies oxidative stress, might lead to oxidative DNA damage, impairs the cellular proliferation process, and results in mutations; all of which increase the possibility for the development of dysfunctional cells, tissue, and organs. The meta-analysis showed that significantly increased frequencies of chromosomal aberrations were seen in type 2 diabetic subjects [80].

3.6. Telomere Shortening

Telomere is a part of a chromosome that prevents the tangling of the chromosome during DNA replication. When a cell divides, the telomere gets slightly shorter each time, and this process continues until the telomere becomes too short, at which point the cell cannot divide anymore, and the cell dies [81]. The main reason for telomere shortening is oxidative stress and incomplete DNA replication [82]. When the shortening of telomeres gets elevated and reaches a critical length, apoptosis is triggered and contributes to cellular senescence or the aging process, potentially impacting overall cellular function [83].

In patients with diabetes or impaired glucose tolerance, excessive oxidative stress induces damage to telomeres and shortens their length [84]. Telomere length is a good surrogate marker for mortality and diabetic complications in diabetic patients. Telomere length in pancreatic beta-cells is also shortened in diabetic patients, potentially leading to an impaired capacity for proliferation and insulin secretion, and accelerated cell death [84]. In an animal model, it has been shown that telomere attrition in adipose tissue induces insulin resistance. Type 2 diabetes is characterized by increased oxidative stress, increased oxidative DNA damage, and senescent retinal and renal phenotypes [85]. Increased oxidative DNA damage and telomere attrition in type 2 diabetes have been suggested to lead to senescent retinal and renal phenotypes (diabetic retinopathy and nephropathy) and senescent vascular endothelial, monocyte-macrophage, and vascular smooth muscle cells (endothelial dysfunction and accelerated atherogenesis) [85].

3.7. Epigenetic Alterations

In epigenetic alterations, DNA methylation, involvement of non-coding RNAs, and modifications to histones play an important role in senescence [86]. DNA methylation is a type of heritable modification that can inhibit gene expression through recruiting gene repression proteins and suppressing the normal transcription factor binding, without altering the original DNA sequences. Aberrant DNA methylation influences cellular functions and may lead to diseases such as CVD, metabolic diseases, and cancer. Cellular senescence, aging, and age-related pathogenesis are the major hallmarks of long non-coding RNAs in aging [87]. A histone is a protein that provides structural support for a chromosome. Each chromosome contains a long molecule of DNA, which must fit into the cell nucleus. To do that, the DNA wraps around complexes of histone proteins, giving the chromosome a more compact shape. In general, histone levels are decreased, and aberrant nucleosome occupancies occur during aging. The accumulation of histone variants is another common feature in the aging process [88]. Methylation and acetylation of histone play an important role in regulating the chromatin structure [89], and such structure changes influence the gene expression patterns associated with senescence [90]. Improper dietary habits and lack of physical exercise are important behavioral factors that increase the risk of obesity, which can affect gene expression through epigenetic modifications [91].

Epigenetic alterations can occur in the early stage of obesity and lead to obesity-related complications [91]. Patients with type 2 diabetes exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets [92]. The epigenetic mechanisms in type 2 diabetes mainly consist of DNA methylation, histone modifications, and regulation by noncoding RNAs [93]. Emerging evidence suggests that oxidative stress can induce aberrant DNA methylation patterns in beta-cells, leading to altered gene expression profiles associated with insulin secretion and cell survival [94]. High glucose induces DNA methyltransferase 1-dependent epigenetic reprogramming of the endothelial exosome proteome in type 2 diabetes [95]. In middle-aged and older Australians, epigenetic age was positively associated with prevalent and incident type 2 diabetes [96].

3.8. Loss of Protein Balance

Aging is associated with a decline in muscle mass, strength, and function, a process known as sarcopenia [97]. This decline is largely attributed to an imbalance between muscle protein synthesis and breakdown, leading to a net loss of muscle protein [97]. This imbalance is influenced by factors like reduced anabolic response to stimuli like food intake and exercise, as well as changes in protein digestion and absorption. The muscle protein synthetic response to the main anabolic stimuli, food intake and physical activity, appears to be blunted in older individuals [98,99,100]. This anabolic resistance is now considered to be a key factor contributing to progressive loss of skeletal muscle mass throughout our lifespan.

Metabolic stress, such as diabetes, can lead to pronounced physiological and cellular adaptations in protein regulation [101], and such pathological conditions can result in muscle atrophy, a net loss of muscle mass, which is highly associated with morbidity [102]. Muscle strength is reduced in individuals with insulin resistance and type 2 diabetes [103,104]. It is plausible that factors derived from adipose tissue can contribute to muscle proteostasis. Isthmin-1 (Ism1), as an important adipokine discovered in recent years, plays a key role in physiological processes such as cell metabolism, energy balance, and insulin sensitivity [105,106]. Ism1 has dual effects of increasing fat and glucose uptake while inhibiting hepatic fat synthesis. Ism1 mitigates diabetes by increasing adipocyte and skeletal muscle glucose uptake by activating the phosphatidylinositol 3'-kinase-Akt pathway [107]. Many studies have shown that the abnormal expression or function of Ism1 is closely related to the occurrence and development of diabetes and its complications. Physiologically, Ism1 ablation in mice results in altered proteostasis, including lower muscle protein levels under fed and fasted conditions, reduced amino acid incorporation into proteins, and reduced phosphorylation of the key protein synthesis effectors Akt and downstream mTORC1 targets [107].

3.9. Deregulated Nutrient Sensing

Deregulated nutrient sensing is a key hallmark of aging, where cellular and organismal processes become less effective at responding to nutrient availability. This dysregulation, particularly in pathways like mTORC1 signaling, can lead to metabolic dysfunction, increased disease susceptibility, and ultimately, contribute to the aging process [108]. The nutrient-sensing network (NSN) is an interlocking network of signaling pathways centered on insulin and insulin-like growth factor-1 (IGF-1), mTORC1, AMPK, and sirtuins (SIRT), and its perturbations promote aging [109]. Lifestyle factors such as diet can modulate NSN [110,111].

3.10. Altered Intercellular Communication

Altered intercellular communication during aging includes the canonical SASP, direct cell-cell communication through gap junctions or tubule-like structures, and long-distance communication, involving extracellular vesicles and paracrine communication mediated by Connexin-containing hemichannels [112].

Extracellular vesicles (EVs) are submicron-sized lipid envelopes that are produced and released from a parent cell and can be taken up by a recipient cell [113]. EVs are capable of mediating cellular signaling by carrying nucleic acids, proteins, lipids, and cellular metabolites between cells and organs. EVs are produced by cells within metabolic tissues, such as adipose tissue, pancreas, muscle, and liver. EV-dependent communication between adipocytes, the vasculature, and immune cells may play an important role in developing type 2 diabetes [113]. Type 2 diabetes involves the loss or dysfunction of pancreatic beta-cells. Impaired Ca2+ uptake into mitochondria, or collapse of a normally interconnected mitochondrial network, is associated with defective insulin secretion [114]. Altered mitochondrial metabolism may also impair beta-cell-beta-cell communication.

3.11. Mitochondrial Dysfunction

Mitochondrial dysfunction is a hallmark of aging, significantly impacting cellular energy, oxidative balance, and calcium levels [115]. It's closely linked to age-associated diseases and is characterized by impaired oxidative phosphorylation, increased oxidative damage, and reduced mitochondrial quality. Mitochondrial dysfunction can also trigger cellular senescence [115].

Type 2 diabetes is characterized by hyperglycemia, hyperlipidemia, and insulin resistance, and such pathological shifts in both circulating fuel levels and energy substrate utilization by central and peripheral tissues contribute to mitochondrial dysfunction across organ systems [116]. The mitochondrion lies at the intersection of critical cellular pathways such as energy substrate metabolism, ROS generation, and apoptosis. Mitochondrial dysfunction leads to impaired oxidative phosphorylation, increased ROS production, mitochondrial DNA damage, and altered mitochondrial dynamics, exacerbating metabolic dysregulation and contributing to diabetic complications [117]. Therefore, mitochondrial dysfunction induces downstream deficits in vital functions, including hepatocyte metabolism, cardiac output, skeletal muscle contraction, beta-cell insulin production, and neuronal health, in type 2 diabetes [116]. Furthermore, the accumulation of mitochondrial DNA mutations and mitochondrial DNA copy number depletion, as well as epigenetic modification of the mitochondrial genome, are associated with the development of type 2 diabetes.

3.12. A Decline in Nicotinamide Adenine Dinucleotide (NAD+)

NAD+ is a crucial coenzyme involved in numerous cellular processes, including energy production and DNA repair. Most of the cellular NAD+ is generated through Nampt activation, a key rate-limiting enzyme that is involved in the salvage pathway. NAD+ is essential for mitochondrial function, and NAD+ acts as a cofactor for enzymes involved in the electron transport chain, a key part of cellular ATP synthesis [118]. Further, NAD+ is known to benefit and restore the body's physiological mechanisms, including DNA replication, chromatin and epigenetic modifications, and gene expression. A decline in NAD+ is strongly linked to the aging process and the development of age-related diseases [119]. As we age, NAD+ levels naturally decrease, potentially impairing these vital cellular functions and contributing to age-related decline and disease [120].

NAD+ is depleted in diabetes, CVD, and neurodegenerative diseases, and in aging [121]. An important hallmark of dysfunctional obese adipose tissue is impaired NAD+/SIRT signaling [122].

3.13. Cellular Senescence

Cellular senescence, a state of irreversible cell cycle arrest, is a key hallmark of aging. It's a cellular response to stress and damage that can contribute to age-related diseases and the overall aging process [123]. Cell senescence accumulation with age can also be detrimental, driving chronic inflammation and tissue dysfunction [124].

Senescence of islet beta-cells has a remarkable impact on the pathogenesis of type 2 diabetes. Islet beta-cells isolated from older mice and those with type 2 diabetes have increased the activity of senescence-associated beta-galactosidase [125]. Furthermore, type 2 diabetes model mice have shown a higher expression level of IGF-1 receptor (IGF-1R) in their beta-cells compared with control mice, indicating a close relationship between pancreatic beta-cell senescence and type 2 diabetes [126]. Studies on aging have revealed that senescent islet beta-cells exhibit reduced insulin secretion ability and less sensitivity to high sugar stimulation [127]. A high-calorie diet can promote fat cell senescence and lead to insulin resistance [128], and insulin resistance can further induce the senescence of pancreatic beta-cells, thereby causing type 2 diabetes [129].

3.14. Stem Cell Exhaustion

Stem cell exhaustion is a significant factor in aging, characterized by a decline in the ability of stem cells to regenerate and maintain tissue homeostasis [130]. Stem cell exhaustion contributes to aging-related decline in tissue function and the development of various diseases.

Individuals with type 2 diabetes may have a reduced ability to revascularize ischemic tissues due to abnormal production of circulating pro-vascular progenitor cells [131]. This 'regenerative cell exhaustion' process is intensified by increasing oxidative stress and inflammation, and during type 2 diabetes progression. Chronic exhaustion may be mediated by changes in the bone marrow microenvironment that dysregulate the wingless-related integration site network, a central pathway maintaining the progenitor cell pool.

The discovery that diabetes reduces circulating stem/progenitor cells and impairs their function has opened an entirely new field of study where diabetology encounters hematology and regenerative medicine [132]. From a clinical perspective, pauperization of circulating stem cells predicts adverse outcomes and death. Diabetes impairs the mobilization of bone marrow stem/progenitor cells, with negative consequences for physiologic hematopoiesis, immune regulation, and tissue regeneration.

3.15. Impaired Macro-Autophagy

Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids, and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development, and survival [133]. There is an age-dependent decline in autophagy, and autophagy is a crucial determinant of cellular health and organismal longevity, and impairment or imbalance in autophagy promotes pathological aging and disease [133]. The decline in macro-autophagy with age has been implicated in various aging-related diseases, including neurodegenerative diseases such as Parkinson's disease and AD, cancer, and CVD [134].

Autophagy-deficient mice showed hypoinsulinemia and hyperglycemia, suggesting that autophagy is necessary to maintain the structure, mass, and function of pancreatic beta-cells [135]. The major nutrient-sensing signal pathways and diabetes-induced altered intracellular metabolism and cellular events, including accumulation of AGEs, increased oxidative stress, endoplasmic reticulum stress, hypoxia, and activation of the renin-angiotensin system, which modulate autophagic activity and contribute to the development of diabetic nephropathy [136]. Enhancing macro-autophagy is important to maintain the fidelity of the secretory apparatus in conditions of high insulin demands, and failures in these adaptive mechanisms are likely to contribute to beta-cell failure [137]. Islet macroautophagic impairment was found in human type 1 diabetes [138]. Altered lysosome content may be associated with lysosome dysfunction before clinical hyperglycemia. Endothelial dysfunction is a key determinant in the pathogenesis of diabetes. Autophagy, a lysosomal recycling process, appears to play an important role in endothelial cells, ensuring endothelial homeostasis and functions. Autophagic flux impairment has been observed in patients with type 1 or type 2 diabetes [139]. Diabetes triggers endothelial autophagy impairment, which contributes to diabetes-mediated endothelial dysfunction.

3.16. The Association Between Hallmarks of Aging and Type 2 Diabetes

The association between hallmarks of aging and type 2 diabetes is shown in Figure 2. Metabolic disorders such as hyperglycemia and insulin resistance observed in type 2 diabetes induce harmful factors such as oxidative stress, inflammation, AGEs, and dysbiosis. Such harmful factors induce impaired maintenance of healthy cells by inducing DNA damage, epigenetic alteration, mitochondrial dysfunction, and worsening type 2 diabetes, and developing diabetic complications. Impaired maintenance of healthy cells is induced by an impaired clearance of senescent cells due to stem cell exhaustion and impaired macro-autophagy. Impaired clearance of senescent cells is unfavorably associated with metabolic disorders and diabetic complications. Thus, type 2 diabetes and aging form a vicious cycle, exacerbating each other's pathology.

4. The Significance of AMPK Activation and mTORC1 Inhibition for Anti-Aging Medicine

AMPK activation is strongly linked to anti-aging mechanisms, as it acts as a cellular energy sensor and regulator that maintains cellular homeostasis, metabolism, stress resistance, and promotes processes like autophagy, all of which are crucial for healthy aging and extended lifespan [140]. Aging results from the progressive dysregulation of several molecular pathways, and mTORC1 and AMPK signaling have been suggested to play a role in the complex changes in key biological networks involved in cellular senescence [141]. AMPK activation and mTORC1 inhibition are closely linked mechanisms involved in the aging process and have shown promise in extending lifespan and mitigating aging-related diseases. AMPK, a cellular energy sensor, becomes activated under low ATP levels, leading to the inhibition of mTORC1, a key pathway involved in cell growth and metabolism that is often dysregulated with age [141].

Effects of AMPK activation and mTOR inhibition on aging-related molecules and aging hallmarks were shown in Figure 3.

Nuclear factor E2-related factor 2 (Nrf2) is activated under oxidative stress conditions, which promotes antioxidant gene expression [142]. Peroxisome proliferator-activated receptor- γ Coactivator 1α (PGC1α) and Nrf2 have been shown to promote each other and regulate the expression of antioxidant genes. Nrf2 is the downstream target of AMPK. Activation of the AMPK/Nrf2 signaling pathway is key to protection from aging-related diseases.

Chronic inflammation associated with increased NF-κB signaling is a typical hallmark of several age-related metabolic disorders [143]. Activators of AMPK have anti-inflammatory properties. Several studies have demonstrated that the activation of AMPK can inhibit NF-κB signaling, a master regulator of inflammation, both in vitro and in vivo [144].

AMPK activation counteracts AGEs by restoring signaling pathways that reduce inflammation and cellular damage [145]. AGEs, formed under hyperglycemia and oxidative stress, induce cellular dysfunction and inflammatory responses by downregulating AMPK activity, whereas AMPK activation can restore these pathways [145]. mTORC1 inhibition has been reported to be a new potential therapeutic target to diminish the accumulation of AGEs, which was possibly due to a protective role of autophagy in the clearance of cytotoxic AGEs [146].

AMPK inactivation is an etiological factor in intestinal dysfunction, and AMPK activation favorably influences intestinal health [147].

AMPK acts as a central regulator of epigenetic processes by phosphorylating histones, DNA methyltransferases, and histone modifiers [148]. Epigenetic modifications play a crucial and complex role in the cellular response to DNA damage, influencing both the detection and repair of DNA lesions and potentially leading to long-term alterations in gene expression [149].

Telomerase reverse transcriptase (TERT) has been known for its telomere-lengthening effect [150]. AMPK-dependent PGC1α upregulation is required for the metformin-induced upregulation of TERT and telomere activity and length [151].

mTORC1 signaling pathway regulates cellular processes relevant to aging, such as cellular and organismal energetics, proteostasis, cell stemness, and cellular senescence. Therefore, mTORC1 inhibition clearly extends life span [152].

Experiments in mammals have demonstrated that AMPK controls autophagy through mTORC1 and Unc-51-like autophagy activating kinase 1 (ULK1) signaling, which augments the quality of cellular housekeeping. The ULK1 complex plays a central role in the initiation stage of autophagy [153]. mTORC1 inhibits the activity of the ULK1 complex by phosphorylating ULK1 and Atg13 [154].

AMPK is a highly conserved sensor of low intracellular ATP levels that is rapidly activated after nearly all mitochondrial stresses [155]. AMPK regulates autophagy and mitophagy through activation of the kinase ULK1 [156]. AMPK phosphorylates mitochondrial fission factor and promotes mitochondrial fission upon energetic stress. By simultaneously regulating mitochondrial fission, mitophagy, and transcriptional control of mitochondrial biogenesis, AMPK acts as a signal integration platform to maintain mitochondrial health.

NAD+ is a vital coenzyme crucial for maintaining mitochondrial function, directly participating in key energy-producing pathways like the tricarboxylic acid cycle and oxidative phosphorylation, and playing a role in cellular signaling and overall homeostasis [157]. Declining NAD+ levels are associated with aging and various chronic diseases, often accompanied by mitochondrial dysfunction, making NAD+ boosting strategies a focus of research for restoring mitochondrial health and combating age-related decline [157]. AMPK controls the expression of genes involved in energy metabolism by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1 [158]. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels.

The anti-aging effects of SIRT1 have been widely studied [159,160]. SIRT1 regulates transcriptional activity and protein expression levels by altering the acetylation status of its substrates, thereby regulating inflammation and stress resistance and suppressing various aging-related effects, including genomic instability, stem cell exhaustion, mitochondrial dysfunction, and telomere shortening. Activating SIRT1 inhibits inflammation by deacetylating NF-κB [161].

The summary of effects of AMPK activation and mTORC1 inhibition on hallmarks of aging is shown in Figure 4.

AMPK activation and mTORC1 inhibition improve every hallmark of aging.

5. Effects of AMPK Activation and mTORC1 Inhibition on Diabetic Complications

Diabetic complications include microangiopathy, such as neuropathy, retinopathy, and nephropathy, and macroangiopathy, such as CVD. The link between AD and type 2 diabetes has been increasingly revealed by research; the danger of developing both AD and type 2 diabetes rises exponentially with age, with type 2 being especially prone to AD [162]. What about the effects of AMPK activation and mTOR inhibition on these diabetic complications and AD?

5.1. Diabetic Neuropathy

Increased ROS, amplified apoptosis, loss of insulinotropic support, neuroinflammation, and decreased autophagy induce the pathogenesis of diabetic neuropathy [163]. Impaired AMPK signaling in dorsal root ganglia neurons is associated with mitochondrial dysfunction and peripheral neuropathy in diabetic models [164]. Activation of AMPK was shown to reverse established losses in thermal sensitivity and epidermal innervation density in streptozotocin-treated rodents [164].

Tang Bi formula (TBF) has been proven effective for diabetic polyneuropathy, while the underlying mechanism remains unclarified. Very recently, TBF ameliorated diabetic polyneuropathy by rectifying mitochondrial dynamic imbalance and modulating the activation of the AMPK-PGC-1α-mitochondrial fusion protein pathway [165].

The altered mTORC1 activity can impair nerve function by affecting essential components like brain-derived neurotrophic factor (BDNF) in Schwann cells, increasing ROS and AGEs, and suppressing beneficial processes like autophagy [166]. Targeting the mTOR pathway with inhibitors or natural compounds shows promise for novel regenerative therapeutic strategies against diabetic complications like neuropathy [167].

5.2. Diabetic Retinopathy (DR)

AMPK is a master metabolic regulator whose activation is being explored as a therapeutic strategy for diabetic retinopathy because it helps maintain cellular energy homeostasis and protects against DR-related complications by modulating stress, inflammation, and cell death. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly discovered adipokine and a vital biomarker, predicting DR severity. CTRP3 prevents diabetes-induced retinal vascular permeability by activating the AMPK signaling pathway [168]

Recently, mTORC1 inhibition has been reported as a novel gene therapeutic strategy for DR [169].

5.3. Diabetic Nephropathy

Renal tubulointerstitial fibrosis was a crucial pathological feature of diabetic nephropathy, and renal tubular injury may be associated with abnormal mitophagy. AMPK agonist metformin ameliorated renal oxidative stress and tubulointerstitial fibrosis in high-fat diet and streptozotocin-induced type 2 diabetic mice via activating the AMPK signal pathway [170].

mTORC1 assumes a pivotal role in cellular division, survival, apoptosis delay, and angiogenesis. It is implicated in diverse signaling pathways and has been observed to partake in the progression of diabetic nephropathy by inhibiting autophagy, promoting inflammation, and increasing oxidative stress [171]. Several studies have reported the inhibitory effect of rapamycin on the development and progression of diabetic kidney disease (DKD) in diabetic animal models [172]. mTORC1 has been considered as a new therapeutic approach for DKD, it is desirable to develop safe mTORC1 modulators in the future.

5.4. CVD

Emerging evidence has suggested that AMPK activators from naturally occurring sources provide notable CV benefits [173]. AMPK activation prevents cardiometabolic disease by its capacity to lower blood pressure, plasma glucose and serum lipids, ROS production, and improve NO bioavailability. AMPK activators thus serve as novel potential drugs in gatekeeping CV health and preventing CVD.

mTORC1 pathway plays a dual role in CVD, promoting processes like atherosclerosis, myocardial infarction, and heart failure through effects on cell growth, metabolism, and inflammation [174]. Inhibiting mTORC1 can offer cardioprotective effects, reducing infarct size and slowing disease progression, making mTORC1 a potential therapeutic target for CVD treatment [175].

5.5. AD

AMPK reduces tau phosphorylation and improves brain function in AD-like model [176]. These findings proved that AMPK might be a new target for AD in the future.

Aberrant mTORC1 signaling is associated with AD pathogenesis, contributing to hallmark pathologies like amyloid beta plaques and tau neurofibrillary tangles through increased production and decreased clearance [177,178]. mTORC1 activation also promotes neuroinflammation, oxidative stress, and cognitive decline, while its inhibition, particularly with drugs like rapamycin, has shown promise in preclinical models for clearing protein aggregates and improving cognitive function [177,178].

6. Effects of Nutritional Interventions and Drugs That Improve Aging Hallmarks by AMPK Activation and mTORC1 Inhibition on Type 2 Diabetes

Effects of nutritional interventions and drugs that improve aging hallmarks by AMPK activation and mTORC1 inhibition on type 2 diabetes are shown in Table 1.

Calorie restriction, vitamin E and C, resveratrol, astaxanthin, and n3-polyunsaturated fatty acids (PUFA) have been reported to have both AMPK-activating and mTORC1-inhibitory effects and to be favorably associated with the incidence, remission, and metabolic parameters of type 2 diabetes.

Drugs used to treat type 2 diabetes, metformin, sodium-glucose co-transporter-2 (SGLT2) inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1RAs), and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs, have been reported to have both AMPK-activating and mTORC1-inhibitory effects.

Imeglimin has been reported to enhance AMPK activity [204], however, the effect of imeglimin on mTORC1 has not yet been reported. However, imeglimin and metformin exert similar pharmacological effects on mitochondrial respiration, AMPK activity, and gene expression [204]. Imeglimin may inhibit mTORC1 in the same way as metformin.

7. Conclusions

Type 2 diabetes accelerates clinical manifestations of aging, such as grey hair and skin aging. Metabolic disorders such as hyperglycemia and insulin resistance observed in type 2 diabetes induce harmful factors such as oxidative stress, inflammation, AGEs, and dysbiosis. Such harmful factors induce impaired maintenance of healthy cells by inducing DNA damage, epigenetic alteration, mitochondrial dysfunction, and worsening type 2 diabetes, and developing diabetic complications. Impaired maintenance of healthy cells is induced by an impaired clearance of senescent cells, due to stem cell exhaustion and impaired macro-autophagy. Impaired clearance of senescent cells is unfavorably associated with metabolic disorders and diabetic complications. Thus, type 2 diabetes and aging form a vicious cycle, exacerbating each other's pathology.

AMPK activation and mTOR inhibition improve every hallmark of aging and are favorably associated with diabetic complications such as diabetic neuropathy, DR, DKD, and AD. Calorie restriction, vitamin E and C, resveratrol, astaxanthin, and n3-PUFA have been reported to have both AMPK-activating and mTORC1-inhibitory effects and to be favorably associated with the incidence, remission, and metabolic parameters of type 2 diabetes. Metformin, SGLT2 inhibitors, GLP-1RAs, and dual GIP/GLP-1 RAs, have been reported to have both AMPK-activating and mTORC1-inhibitory effects. The therapeutic interventions that activate AMPK and inhibit mTORC1 may be optimal treatments for type 2 diabetes.