Why We Age: Deregulated Nutrient Sensing

Aging is a combination of complex processes influenced by various biological pathways, one of which is the regulation of nutrient sensing. The “Hallmarks of Aging” framework identifies deregulated nutrient sensing as a key contributor to aging [1]. Four primary nutrient-sensing pathways regulate metabolism and impact aging: the insulin and insulin-like growth factor (IIS) pathway, mechanistic target of rapamycin (mTOR), sirtuins, and AMP-activated protein kinase (AMPK) [2]. These pathways are termed “nutrient-sensing” because their activities are modulated by nutrient availability. Dysregulation in these pathways can lead to metabolic imbalances and accelerate aging.

IGF-1 and the insulin/IGF-1 signaling (IIS) pathway

The IIS pathway, a pivotal regulator of growth, metabolism, and aging, integrates insulin and insulin-like growth factor 1 (IGF-1) signals. IGF-1, a hormone structurally similar to insulin, is primarily involved in growth and development.

It binds to the IGF-1 receptor on the surface of cells in the hypothalamus, initiating signaling cascades that influence cellular proliferation and metabolism. Both insulin and IGF-1 are key contributors to glucose homeostasis and are central to the IIS pathway [3].

Attenuation of the IIS pathway

Studies in various model organisms have demonstrated that reduced IIS pathway activity can extend lifespan. In worms (Caenorhabditis elegans), mutations that decrease IIS signaling result in significant lifespan extension. Reduced activity of the DAF-2 receptor (analogous to the insulin/IGF-1 receptor) leads to activation of the DAF-16 transcription factor (a homolog of mammalian FOXO), which promotes the expression of genes involved in stress resistance and longevity [4]. Similarly, in fruit flies (Drosophila melanogaster), reduced IIS signaling activates dFOXO, enhancing stress response mechanisms and extending lifespan [5]. Mice with mutations that diminish IIS pathway components, such as insulin receptor substrate (IRS) proteins and IGF-1 receptor haploinsufficiency, show extended lifespans and improved metabolic profiles [6].

Attenuation of IIS leads to decreased activation of the AKT kinase, resulting in reduced phosphorylation of FOXO transcription factors. Unphosphorylated FOXO translocates to the nucleus, activating genes associated with DNA repair, antioxidant defense, and cellular stress responses. The activation of FOXO factors enhances the organism’s ability to cope with oxidative stress and other age-related damages, contributing to increased lifespan and healthspan [7].

IGF-1’s dual role in healthspan and disease

While reduced IIS activity can promote longevity, IGF-1 is essential in maintaining healthspan. It stimulates protein synthesis and muscle growth, which are crucial for maintaining muscle mass and strength. Adequate IGF-1 levels help prevent sarcopenia in older people [8, 9]. IGF-1 also supports neuronal survival and function, potentially mitigating age-related cognitive decline [10-12]. However, high levels of IGF-1 can enhance cell proliferation and inhibit apoptosis, processes that, while beneficial for growth and repair, may increase the risk of cancer development due to unchecked cell division. Elevated circulating IGF-1 levels have been correlated with a higher risk of certain cancers, such as prostate, breast, and colorectal cancers [13-15].

Complexities and mechanistic insights

The relationship between IIS activity and aging is complex and context-dependent. Contrary to the expectation that high IIS activity accelerates aging, studies have found that IIS activity often declines in aged organisms. This decline may contribute to age-related metabolic impairments and reduced regenerative capacity. The decrease in IIS activity with age is likely due to alterations in hormone production and receptor sensitivity, not an adaptive mechanism to promote longevity [16-18].

Lifelong or early-life reduction of IIS activity can activate protective stress response pathways, enhancing longevity. However, sudden attenuation of IIS in older organisms may not provide the same benefits and could impair essential functions such as glucose metabolism and tissue repair. In aged individuals, IGF-1 supplementation may improve healthspan by enhancing muscle mass, bone density, and cognitive function. Supplementation must be approached cautiously due to the potential increased risk of cancer and the complexity of IIS interactions with other metabolic pathways [13,15].

IGF-1 and human longevity

The effects of IGF-1 on human aging and longevity are still under investigation. People with Laron syndrome have mutations in the growth hormone receptor, leading to low IGF-1 levels. They exhibit short stature and are reported to have a reduced incidence of cancer and diabetes. Despite lower rates of certain diseases, there is no clear evidence that people with Laron syndrome have extended lifespans compared to the general population [19-21].

Research has identified variants in the IGF-1 receptor gene among centenarians, suggesting that altered IIS may contribute to exceptional longevity [22]. However, longevity is influenced by genetic, environmental, and lifestyle factors, making it challenging to attribute extended lifespan solely to IIS pathway alterations. Factors such as diet, physical activity, and comorbid conditions affect IGF-1 levels and complicate the assessment of its impact on aging. Studies have yielded mixed results, and more research is needed to clarify the role of IGF-1 in human longevity.

Reconciling the dichotomy

The differing effects of IIS modulation can be understood by considering the timing and context of its alteration. Reducing IIS activity throughout or early in life can activate protective stress response pathways, enhance DNA repair mechanisms, and promote longevity. Activating FOXO transcription factors leads to the expression of genes associated with stress resistance and metabolic homeostasis [23]. On the other hand, sudden reduction of IIS activity in later life may not allow sufficient time for protective mechanisms to confer benefits. Aged tissues may have a diminished capacity to respond adaptively. Lowered IIS activity in the elderly can exacerbate issues like insulin resistance, decreased tissue repair, and increased frailty [18].

IGF-1 and human lifespan

The role of IGF-1 in human aging and longevity remains an area of active research with conflicting evidence. People with Laron syndrome have mutations in the growth hormone receptor, resulting in low IGF-1 levels.

They exhibit lower rates of cancer and diabetes; however, there is no clear evidence that they have extended lifespans compared to the general population [19]. Some studies have found associations between reduced IGF-1 signaling and longevity in specific populations, such as female nonagenarians and centenarians [22]. These findings should be embraced with caution due to potential confounding factors.

Studies on IGF-1 and human lifespan are inconsistent due to variables like nutrition, lifestyle, and genetic diversity. IGF-1 levels are influenced by various factors, making it difficult to establish a direct causal relationship between IGF-1 activity and lifespan.

Mechanistic target of rapamycin (mTOR)

The mechanistic target of rapamycin (mTOR) is a central regulator of cellular growth, metabolism, and aging. It forms two distinct complexes, mTORC1 and mTORC2, which respond to nutrient availability, particularly amino acids. mTOR functions as a kinase, phosphorylating target proteins to regulate protein synthesis, autophagy, and lipid metabolism [24].

mTORC1 promotes protein synthesis by activating ribosomal protein S6 kinase (S6K) and inhibiting eukaryotic translation initiation factor 4E-binding protein (4E-BP1). By stimulating anabolic pathways, mTOR supports cell growth and proliferation, similar to the IIS pathway. mTORC1 activity is upregulated in the presence of abundant amino acids, linking nutrient availability to growth signals [25].

mTOR activity and lifespan extension

Reduced mTOR signaling has been linked to lifespan extension in various model organisms. In yeast, worms, and flies, genetic or pharmacological inhibition of mTOR extends lifespan by enhancing stress resistance and autophagy [26].

Treatment with rapamycin, an mTOR inhibitor, increases lifespan and improves health markers in mice [27]. Reduced mTORC1 activity leads to autophagy induction, allowing the removal of damaged proteins and organelles. Lower mTOR signaling enhances the cellular stress response, contributing to longevity [28].

Studies have found that mTOR activity increases in the hypothalami of aged mice, contributing to age-related metabolic dysregulation and obesity. Elevated mTOR signaling in aging can lead to insulin resistance and impaired metabolic homeostasis [29].

Rapamycin treatment in aged mice reduces mTOR activity, improving metabolic parameters and extending lifespan. However, chronic inhibition of mTOR can have adverse effects, such as impaired wound healing, glucose intolerance, and reproductive issues [27].

Balancing mTOR activity

While reduced mTOR activity can have anti-aging effects, excessively low mTOR signaling can be detrimental. mTOR is essential for cell proliferation during tissue repair, and over-inhibition may lead to insulin resistance and glucose intolerance.

Prolonged mTOR inhibition can cause testicular degeneration in animal models. The benefits of mTOR inhibition depend on the degree and timing of intervention. Careful modulation is necessary to maximize benefits and minimize risks [27].

Both the IIS pathway and mTOR are integral to regulating metabolism, growth, and aging. Attenuation of these pathways can promote longevity in model organisms through mechanisms involving enhanced stress resistance, autophagy, and metabolic regulation.

However, the relationship is nuanced, and modulation must consider timing, dosage, and individual physiological contexts to avoid adverse effects. Understanding the complexities of IIS and mTOR pathways provides valuable insights for developing targeted interventions to promote healthy aging.

Sirtuins and aging

Sirtuins are a family of proteins that function as NAD-dependent deacetylases and ADP-ribosyltransferases, playing crucial roles in regulating cellular metabolism, genome stability, and aging processes. In mammals, there are seven sirtuin proteins (SIRT1 to SIRT7), each of which is localized in different cellular compartments and involved in various biological functions [30, 31].

Sirtuins remove acetyl groups from lysine residues on histone proteins, leading to a more condensed chromatin structure and altered gene expression. By modulating histone acetylation, sirtuins influence the accessibility of DNA to transcriptional machinery, thereby regulating gene expression in response to cellular metabolic status. They also deacetylate various non-histone proteins involved in metabolism, stress responses, and DNA repair, affecting their activity and stability [30, 32].

NAD⁺ dependence and energy sensing

Sirtuins require NAD⁺ for their deacetylase activity, linking their function to the cell’s metabolic state. High NAD⁺ levels, which occur during low energy availability, activate sirtuins. During caloric restriction or fasting, increased NAD⁺ levels enhance sirtuin activity, promoting adaptations that support cellular survival under energy stress [33, 34].

Sirtuins in longevity and healthspan

SIRT1 regulates pathways involved in stress resistance, inflammation, and metabolism [35]. It deacetylates key transcription factors such as PGC-1α, FOXO, and NF-κB [36-38]. Overexpression of SIRT1 in mice improves metabolic functions and reduces age-related diseases but does not significantly extend lifespan [39]. SIRT1 activation promotes mitochondrial function through deacetylation of PGC-1α, enhancing energy efficiency [40]. By deacetylating FOXO transcription factors, SIRT1 enhances antioxidant defenses and DNA repair mechanisms [7].

SIRT6 has been shown to extend lifespan when overexpressed in mice, particularly in males [41]. It is involved in DNA repair and maintenance of telomere integrity, which is crucial for preventing aging-associated genomic instability. SIRT6 influences glucose and lipid metabolism by regulating genes involved in glycolysis and fatty acid oxidation [42].

SIRT3 is primarily located in the mitochondria and regulates the acetylation status of mitochondrial proteins. By deacetylating and activating antioxidant enzymes like superoxide dismutase 2 (SOD2), SIRT3 reduces reactive oxygen species (ROS) [43, 44]. Overexpression of SIRT3 enhances the regenerative capacity of aged hematopoietic stem cells by improving mitochondrial function [45].

In lower organisms like yeast and worms, overexpression of SIR2 has been shown to extend lifespan through mechanisms involving enhanced genomic stability and stress resistance in some studies [46, 47]. However, the effects of SIR2 overexpression can vary based on environmental conditions and genetic background [48].

In mammals, sirtuin activation often improves healthspan, reducing age-related diseases, without necessarily extending overall lifespan. Differences in metabolism and physiology between species make it difficult to generalize sirtuin effects from model organisms to humans. Compounds like resveratrol that activate sirtuins show promise but have varying efficacy in different models [49].

AMP-activated protein kinase (AMPK)

AMPK is a central energy sensor that maintains cellular energy homeostasis. It is activated in response to increases in AMP and ADP levels relative to ATP, indicating a low-energy state [50].

The binding of AMP or ADP to the γ-subunit of AMPK induces a conformational change, promoting its activation. AMPK is also activated by phosphorylation at a specific threonine residue (Thr172) by upstream kinases like liver kinase B1 (LKB1) under energy stress. AMPK stimulates catabolic pathways that generate ATP, such as glucose uptake and fatty acid oxidation. It inhibits energy-consuming processes like lipid and protein formation along with gluconeogenesis by phosphorylating key enzymes and regulatory proteins [50].

AMPK in longevity and healthspan

AMPK activates lifespan in organisms such as C. elegans and Drosophila by enhancing stress resistance and metabolic efficiency [51, 52]. AMPK activation promotes autophagy, aiding in removing damaged organelles and proteins. It improves mitochondrial function, reducing oxidative damage associated with aging [53]. Pharmacological activation of AMPK, such as with metformin, indirectly increases AMP levels by inhibiting mitochondrial complex I. In animal models, metformin extends lifespan and delays the onset of age-related diseases [54].

AICAR, an AMP analog directly activating AMPK, shows protective effects against metabolic disorders [55]. Caloric restriction increases the AMP/ATP ratio, activating AMPK and mimicking the effects of low-energy states. AMPK activation can increase NAD⁺ levels, enhance sirtuin activity, and promote coordinated metabolic responses [53].

Impaired AMPK signaling is associated with decreased insulin sensitivity and glucose uptake. Reduced AMPK activity increases lipid synthesis and storage, contributing to obesity. Lower AMPK activity results in decreased antioxidant defenses, increasing oxidative damage. AMPK negatively regulates inflammatory signaling pathways, and its reduction can exacerbate age-related inflammation [53].

Interplay between AMPK, sirtuins, and mTOR

AMPK can enhance NAD⁺ synthesis, activating sirtuins. Sirtuins can deacetylate and activate LKB1, leading to further AMPK activation. This interplay ensures a coordinated response to energy stress, promoting catabolic processes and inhibiting anabolic pathways [56]. AMPK phosphorylates and activates tuberous sclerosis complex 2 (TSC2) and raptor, inhibiting mTORC1 activity. By inhibiting mTORC1, AMPK promotes autophagy, contributing to cellular maintenance and longevity [57].

Sirtuins and AMPK are integral components of the cellular nutrient-sensing network that regulate metabolism, stress responses, and aging. Their activation under low-energy conditions promotes adaptive responses that enhance healthspan and, in some cases, extend lifespan in model organisms. Understanding the mechanistic roles of these pathways provides insights into potential therapeutic targets for age-related diseases and interventions to promote healthy aging.

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