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This report is written by MaltSci based on the latest literature and research findings

How does cellular metabolism regulate aging? ​

Abstract ​

Aging is a multifaceted biological phenomenon marked by a progressive decline in physiological functions and an increased vulnerability to age-related diseases. Recent studies have revealed that cellular metabolism plays a critical role in regulating aging, influencing energy production, cellular repair, growth, and apoptosis. This review synthesizes current knowledge on how metabolic alterations contribute to aging, focusing on the interplay between metabolism and various cellular processes. Key findings highlight that aging is associated with significant metabolic reprogramming in immune cells, stem cells, and tissues, leading to a state of 'inflammaging' characterized by chronic low-grade inflammation. Additionally, mitochondrial dysfunction emerges as a hallmark of aging, impacting cellular bioenergetics and contributing to various age-related disorders. Nutrient sensing pathways, particularly the insulin/IGF-1 and mTOR pathways, are implicated in the regulation of aging processes, influencing longevity and cellular metabolism. Furthermore, oxidative stress, arising from metabolic dysregulation, exacerbates cellular damage and aging phenotypes. Therapeutic interventions, including caloric restriction, fasting, and pharmacological agents targeting metabolic processes, show promise in mitigating the effects of aging and enhancing healthspan. Understanding the complex relationship between cellular metabolism and aging is crucial for developing effective strategies to promote healthy aging and improve quality of life as the global population ages.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Cellular Metabolism Overview
    • 2.1 Definition and Key Pathways
    • 2.2 Metabolic Changes with Age
  • 3 Role of Mitochondrial Function in Aging
    • 3.1 Mitochondrial Biogenesis and Dynamics
    • 3.2 Mitochondrial Dysfunction and Aging
  • 4 Impact of Nutrient Sensing on Aging
    • 4.1 Insulin/IGF-1 Signaling Pathway
    • 4.2 mTOR Pathway and Aging
  • 5 Oxidative Stress and Aging
    • 5.1 Sources of Reactive Oxygen Species
    • 5.2 Antioxidant Defense Mechanisms
  • 6 Therapeutic Interventions Targeting Metabolism
    • 6.1 Caloric Restriction and Fasting
    • 6.2 Pharmacological Agents and Metabolic Modulators
  • 7 Conclusion

1 Introduction ​

Aging is a multifaceted biological phenomenon characterized by a progressive decline in physiological functions and an increased susceptibility to various age-related diseases. This complex process is driven by a myriad of factors, including genetic, environmental, and lifestyle influences. Among these, cellular metabolism has emerged as a critical regulator of aging, affecting not only energy production but also cellular repair, growth, and apoptosis. Recent studies have illuminated the intricate relationship between cellular metabolism and aging, highlighting how metabolic alterations can lead to detrimental effects such as increased oxidative stress, mitochondrial dysfunction, and impaired nutrient sensing, which collectively contribute to the aging phenotype [1][2].

The significance of understanding the interplay between cellular metabolism and aging cannot be overstated. As the global population ages, the burden of age-related diseases continues to escalate, posing significant challenges to public health systems. Identifying the metabolic changes that accompany aging and elucidating their consequences on cellular function is crucial for developing effective interventions aimed at promoting healthy aging and extending healthspan. Recent research has underscored the potential for targeting metabolic pathways to mitigate the adverse effects of aging, paving the way for novel therapeutic strategies that could enhance longevity and quality of life [3][4].

Current research has revealed that aging is associated with significant metabolic reprogramming across various cell types, including immune cells, stem cells, and tissues such as bone and muscle. These metabolic changes often result in a state termed "inflammaging," characterized by chronic low-grade inflammation that exacerbates age-related decline [5][6]. Furthermore, the role of mitochondrial function in aging has gained considerable attention, with studies demonstrating that mitochondrial dysfunction is a hallmark of aging that impacts cellular bioenergetics and contributes to various age-related disorders [7][8]. Additionally, nutrient sensing pathways, such as the insulin/IGF-1 and mTOR pathways, have been implicated in the regulation of aging processes, influencing cellular metabolism and longevity [2][9].

This review is organized into several key sections that explore the relationship between cellular metabolism and aging. We will begin with an overview of cellular metabolism, defining its key pathways and discussing how metabolic changes manifest with age. Next, we will delve into the role of mitochondrial function in aging, examining both mitochondrial biogenesis and the consequences of mitochondrial dysfunction. Following this, we will investigate the impact of nutrient sensing on aging, focusing on critical pathways such as insulin/IGF-1 signaling and mTOR. The discussion will then shift to oxidative stress, highlighting its sources and the body's antioxidant defense mechanisms. Finally, we will explore therapeutic interventions targeting metabolic processes, including caloric restriction, fasting, and pharmacological agents, that hold promise for mitigating the effects of aging and enhancing healthspan.

In summary, understanding how cellular metabolism regulates aging is essential for developing strategies to combat age-related decline and improve the quality of life in an aging population. By synthesizing current knowledge on metabolic pathways and their implications for aging, this review aims to provide a comprehensive overview of the field and highlight future directions for research and therapeutic development.

2 Cellular Metabolism Overview ​

2.1 Definition and Key Pathways ​

Cellular metabolism plays a critical role in the aging process, influencing various biological functions and contributing to age-related decline in tissue homeostasis and regenerative capacity. Metabolism encompasses the biochemical processes that convert nutrients into energy and building blocks, essential for cellular function, growth, and maintenance. Key pathways involved in cellular metabolism include glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and lipid metabolism, all of which undergo significant alterations with age.

Aging is associated with a decline in cellular metabolic function, leading to impaired energy production and increased oxidative stress. This metabolic decline is evident in various cell types, including immune cells, stem cells, and osteoblasts. For instance, T cells experience metabolic reprogramming during aging, characterized by increased glycolytic and mitochondrial fluxes in memory T cells, which results in heightened production of reactive oxygen species (ROS) and proinflammatory cytokines, contributing to a state known as "inflammaging" (Chen et al., 2022; Ginefra et al., 2024). The chronic low-grade inflammation associated with inflammaging is a significant factor in the deterioration of immune function and increased susceptibility to age-related diseases.

In stem cells, metabolic plasticity is crucial for maintaining self-renewal and differentiation capabilities. Aging triggers stem cell senescence, marked by diminished proliferative capacity and altered metabolic states. The interplay between metabolism and epigenetic modifications in stem cells influences their fate decisions, with nutrient-sensitive metabolites acting as regulators of cellular behavior (Wei et al., 2025). Metabolic reprogramming in aged stem cells can lead to compromised tissue regeneration and contribute to age-related disorders, such as neurodegeneration and cardiovascular diseases.

Bone metabolism also reflects the impact of aging on cellular metabolism. In osteoblasts, aging is associated with mitochondrial dysfunction and a lack of metabolic flexibility, leading to lipid accumulation and oxidative stress, which are implicated in age-related bone loss (Nandy et al., 2024). These metabolic alterations in osteoblasts contribute to the pathogenesis of osteoporosis, highlighting the significance of metabolic health in maintaining skeletal integrity.

Furthermore, the metabolic landscape of hematopoietic stem cells (HSCs) is altered during aging, affecting hematopoietic output and increasing the risk of leukemogenesis (Chiang et al., 2025). The relationship between metabolic dysfunction and HSC aging underscores the importance of understanding metabolic pathways as potential therapeutic targets for rejuvenating stem cell function and mitigating age-related decline.

Overall, cellular metabolism serves as a fundamental regulator of aging, influencing various pathways that determine cellular function, immune response, and tissue regeneration. The intricate crosstalk between metabolic processes and aging presents opportunities for developing innovative interventions aimed at promoting healthspan and longevity through metabolic reprogramming and targeted therapies. Understanding these mechanisms is crucial for addressing the challenges posed by aging populations and associated diseases.

2.2 Metabolic Changes with Age ​

Cellular metabolism plays a pivotal role in regulating aging, with significant metabolic changes observed as organisms age. Aging is characterized by a progressive decline in cellular and functional capabilities, which is intricately linked to alterations in metabolic pathways. These metabolic changes are not only a hallmark of aging but also contribute to the pathogenesis of various age-related diseases.

One of the critical aspects of aging is the phenomenon known as "inflammaging," a chronic low-grade inflammation that arises due to metabolic dysregulation in immune cells, particularly T cells. Aging T cells exhibit altered metabolic programs, leading to increased production of reactive oxygen species (ROS) and pro-inflammatory cytokines, which can further exacerbate tissue inflammation and dysfunction (Chen et al., 2022) [10]. This metabolic reprogramming in T cells has been shown to be a significant contributor to the decline in immune function with age, highlighting the importance of metabolism in immune senescence (Ginefra et al., 2024) [3].

In stem cells, metabolic plasticity is essential for maintaining their self-renewal and differentiation capabilities. Aging leads to stem cell senescence, which is marked by a decline in proliferative capacity and differentiation potential. This senescence is influenced by metabolic alterations that affect the signaling pathways governing stem cell fate decisions. Specifically, nutrient-sensitive metabolites and their interactions with epigenetic modifiers create a metabolism-epigenetic axis that is crucial for regulating stem cell behavior and maintaining tissue homeostasis (Wei et al., 2025) [2].

Moreover, the aging process significantly impacts the metabolism of osteoblasts, the cells responsible for bone formation. Research indicates that aged osteoblasts exhibit mitochondrial dysfunction and impaired metabolic flexibility, leading to lipid accumulation and oxidative stress, which are implicated in age-related bone loss (Nandy et al., 2024) [4]. This disruption in metabolic handling of substrates in osteoblasts not only contributes to osteoporosis but also exemplifies how aging alters cellular metabolism across different tissue types.

The overall metabolic landscape in aging is marked by a decline in mitochondrial function and changes in nutrient metabolism, including glucose and lipid metabolism. For instance, aging is associated with increased oxidative stress and altered energy production pathways, which can lead to cellular damage and dysfunction (Raza, 2024) [6]. These metabolic changes are further compounded by factors such as hormonal signaling and nutrient sensing, which can exacerbate the aging process (van Beek et al., 2016) [11].

In summary, cellular metabolism is intricately linked to the aging process through various mechanisms that involve metabolic reprogramming in immune cells, stem cell senescence, and the functional decline of other cell types. Understanding these metabolic alterations provides valuable insights into potential therapeutic strategies aimed at mitigating age-related decline and enhancing healthspan.

3 Role of Mitochondrial Function in Aging ​

3.1 Mitochondrial Biogenesis and Dynamics ​

Cellular metabolism plays a crucial role in regulating aging, primarily through the function of mitochondria, which are essential organelles responsible for energy production and various metabolic processes. Mitochondria are not only vital for ATP generation from glucose and fatty acids but also contribute to amino acid metabolism, phospholipid modifications, and calcium regulation [12]. As organisms age, mitochondrial function declines, leading to a range of age-related disorders and metabolic diseases. This decline is often associated with the deregulation of cellular metabolism and mitochondrial dysfunction, which is a significant factor in the aging process [12].

Mitochondrial biogenesis and dynamics—encompassing processes such as mitochondrial fission and fusion—are integral to maintaining mitochondrial health and functionality. These processes are regulated by key nutritional sensors, including mTOR, AMPK, and Sirtuins, which influence mitochondrial turnover through mechanisms like mitophagy [12]. The balance between mitochondrial fusion and fission is essential for maintaining mitochondrial morphology and function. A decline in this balance can lead to the accumulation of damaged mitochondria, contributing to oxidative stress and cellular dysfunction, which are hallmarks of aging [13].

Mitochondrial dynamics also play a role in how cells respond to metabolic demands and stressors. As aging progresses, the ability of mitochondria to adapt to these changes diminishes, leading to impaired energy production and increased production of reactive oxygen species (ROS) [12]. The accumulation of ROS can further damage mitochondrial DNA and proteins, creating a vicious cycle that exacerbates cellular aging [14].

Furthermore, recent studies indicate that mitochondrial dysfunction can lead to chronic inflammation, which is a significant factor in aging and age-related diseases [15]. Mitochondria can release damage-associated molecular patterns (DAMPs) that trigger inflammatory responses, contributing to the aging process and increasing susceptibility to age-related pathologies [15].

The regulation of mitochondrial function through metabolic pathways is also linked to longevity. For instance, interventions such as caloric restriction and exercise have been shown to enhance mitochondrial biogenesis and improve metabolic health, thereby promoting healthier aging [16]. These interventions activate signaling pathways that improve mitochondrial function and increase the turnover of dysfunctional mitochondria, thereby reducing the impact of aging on cellular metabolism [16].

In summary, cellular metabolism, particularly through the regulation of mitochondrial function, biogenesis, and dynamics, plays a pivotal role in the aging process. Maintaining mitochondrial health is crucial for preserving metabolic balance, reducing oxidative stress, and preventing the onset of age-related diseases. Understanding these mechanisms provides insights into potential therapeutic strategies aimed at promoting healthy aging and extending lifespan.

3.2 Mitochondrial Dysfunction and Aging ​

Cellular metabolism plays a crucial role in regulating aging, particularly through the function and dysfunction of mitochondria. Mitochondria, known as the powerhouses of the cell, are integral to cellular bioenergetics and metabolic processes. They not only produce adenosine triphosphate (ATP) but also participate in various essential functions such as calcium regulation, reactive oxygen species (ROS) production, and apoptosis. As organisms age, mitochondrial function declines, leading to a cascade of metabolic disturbances that contribute to the aging process and the development of age-related diseases.

Aging is characterized by a progressive impairment of cellular functions, with mitochondrial dysfunction being a central aspect of this decline. Mitochondria are involved in key metabolic pathways, and their dysfunction can result in decreased ATP production and increased oxidative stress due to the overproduction of ROS. This accumulation of ROS can lead to oxidative damage to cellular components, including DNA, proteins, and lipids, which is a significant factor in the aging process (López-Lluch et al. 2015; Natarajan et al. 2020).

Mitochondrial dysfunction is linked to several age-related diseases, including neurodegenerative disorders, metabolic syndromes, and cardiovascular diseases. The decline in mitochondrial health is often associated with an imbalance in metabolic pathways regulated by key nutritional sensors such as mTOR, AMPK, and sirtuins. These sensors control mitochondrial biogenesis and dynamics, influencing the balance between mitochondrial fission, fusion, and mitophagy—the process by which damaged mitochondria are removed (Wei et al. 2025; Amorim et al. 2022).

As aging progresses, the capacity for mitochondrial biogenesis and the efficiency of mitophagy decline, leading to an accumulation of dysfunctional mitochondria. This accumulation exacerbates oxidative stress and contributes to cellular senescence, further promoting age-related decline (Somasundaram et al. 2024; McGuire 2019). In addition, altered mitochondrial dynamics and impaired energy metabolism can disrupt cellular homeostasis, affecting not only energy production but also cellular signaling pathways that are vital for maintaining tissue health (Batalha et al. 2022; Tran & Reddy 2020).

Moreover, recent studies have highlighted the importance of mitochondrial metabolic reprogramming as a potential therapeutic strategy to mitigate the effects of aging. By targeting mitochondrial function, researchers aim to restore cellular metabolism, enhance mitochondrial biogenesis, and improve overall cellular health, thereby potentially extending healthspan and lifespan (Lee et al. 2021; Bartman et al. 2024).

In summary, mitochondrial function is central to cellular metabolism and plays a pivotal role in the aging process. Mitochondrial dysfunction leads to a decline in energy production and an increase in oxidative stress, which collectively contribute to cellular senescence and age-related diseases. Understanding the mechanisms underlying mitochondrial dysfunction and its impact on cellular metabolism is crucial for developing effective interventions aimed at promoting healthy aging and preventing age-related pathologies.

4 Impact of Nutrient Sensing on Aging ​

4.1 Insulin/IGF-1 Signaling Pathway ​

Cellular metabolism plays a critical role in the regulation of aging, particularly through the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. This pathway is evolutionary conserved and has been implicated in various functions necessary for metabolism, growth, and reproduction across species, including Caenorhabditis elegans, Drosophila melanogaster, and mammals. Notably, the insulin/IGF-1 signaling pathway is central to the modulation of longevity and age-related diseases.

The insulin/IGF-1 signaling pathway influences cellular metabolism by regulating protein and energy metabolism, as well as the proliferation and differentiation of insulin/IGF-1-responsive cells. In model organisms, reduced activity of this pathway has been associated with lifespan extension, while increased activity tends to accelerate the aging process. Specifically, studies have shown that in C. elegans, the insulin/IGF-1 pathway acts during adulthood to influence aging, suggesting that the timing of signaling is crucial for longevity outcomes (Dillin et al., 2002) [17].

At the cellular level, the activation of insulin/IGF-1 receptors stimulates the STAT3 signaling pathway through JAK and AKT-driven mechanisms. This activation promotes the development of immunosuppressive cells, which help counteract chronic low-grade inflammation associated with aging. However, prolonged activation of STAT3 also leads to a negative feedback response via the induction of suppressor of cytokine signaling (SOCS) factors, which inhibit insulin/IGF-1 receptor activity and contribute to insulin resistance, a condition exacerbated by aging (Salminen et al., 2021) [18].

Moreover, the insulin/IGF-1 signaling pathway has been shown to influence gene expression related to oxidative stress response, heat shock, metabolism, and autophagy, mediated by FOXO transcription factors (Murphy et al., 2003) [19]. The interplay between these signaling pathways is essential for maintaining cellular homeostasis and mitigating age-related decline.

The paradoxical role of insulin/IGF-1 signaling in longevity is highlighted by studies indicating that while disruption of this pathway can extend lifespan in simpler organisms, similar disruptions in mammals can lead to increased susceptibility to age-related diseases (Rincon et al., 2004) [20]. This complexity arises from the distinct metabolic pathways and receptor interactions present in mammals, which differ significantly from those in invertebrates.

Recent research has also indicated that elevated IGF-1 levels are associated with cellular senescence, particularly in hair follicle stem cells, leading to premature aging phenotypes (Wang et al., 2025) [21]. Interventions that target IGF-1 signaling, such as dietary restrictions or pharmacological approaches to modulate its activity, have shown promise in mitigating age-related changes and enhancing longevity.

In summary, the insulin/IGF-1 signaling pathway serves as a crucial nexus between nutrient sensing and aging, regulating metabolic processes that ultimately influence cellular senescence, stress resistance, and the onset of age-related diseases. The intricate balance of this pathway's activity is vital for understanding the biological mechanisms of aging and developing potential therapeutic strategies for age-related conditions.

4.2 mTOR Pathway and Aging ​

Cellular metabolism plays a pivotal role in regulating aging, primarily through the mechanistic target of rapamycin (mTOR) signaling pathway, which is a central regulator of cellular metabolism and nutrient sensing. The mTOR pathway integrates various environmental cues, including nutrient availability, growth factors, and energy status, to control key cellular processes such as protein synthesis, autophagy, and metabolism. Dysregulation of mTOR signaling has been implicated in aging and age-related diseases.

The mTOR pathway, particularly mTOR complex 1 (mTORC1), is crucial in modulating lifespan and healthspan by influencing cellular processes that are fundamental to aging. It regulates protein synthesis and autophagy, both of which are essential for maintaining cellular homeostasis and function. Studies have shown that mTORC1 controls the balance between anabolic and catabolic processes, which is vital for cellular health. When mTORC1 is hyperactivated, it can lead to impaired autophagy, resulting in the accumulation of damaged proteins and organelles, a hallmark of aging (Dai et al., 2023; Liu & Sabatini, 2020).

Research has demonstrated that the inhibition of mTOR signaling, for instance through caloric restriction or the use of mTOR inhibitors like rapamycin, can extend lifespan and delay the onset of age-related diseases across various model organisms. This suggests that the downregulation of mTOR activity mimics the effects of caloric restriction, promoting longevity and enhancing metabolic health (Raghuvanshi et al., 2025; Antikainen et al., 2017).

Moreover, the regulation of autophagy by mTOR is particularly significant in the context of aging. Autophagy is a cellular process that degrades and recycles cellular components, which is essential for removing damaged organelles and proteins. As organisms age, the efficiency of autophagy declines, leading to the accumulation of cellular debris and contributing to aging phenotypes (Markaki & Tavernarakis, 2013). The mTOR pathway inhibits autophagy under nutrient-rich conditions, thereby reducing the cellular capacity to cope with stress and maintain metabolic homeostasis (Sung et al., 2018).

The interplay between mTOR signaling and other metabolic pathways also underscores its role in aging. For instance, mTOR interacts with cellular energy sensors like AMP-activated protein kinase (AMPK) and plays a role in glucose and lipid metabolism, which are critical for maintaining cellular function throughout the lifespan (Wei et al., 2015). This intricate regulation indicates that the mTOR pathway not only governs metabolic responses but also influences the aging process by modulating how cells respond to metabolic stress and nutrient availability.

In summary, cellular metabolism regulates aging significantly through the mTOR signaling pathway, which integrates nutrient sensing with cellular growth and metabolism. Dysregulation of this pathway can lead to age-related pathologies, while its modulation via dietary interventions or pharmacological agents presents potential therapeutic strategies for extending lifespan and improving health during aging.

5 Oxidative Stress and Aging ​

5.1 Sources of Reactive Oxygen Species ​

Cellular metabolism plays a critical role in the regulation of aging, primarily through the production and management of reactive oxygen species (ROS). The process of cellular metabolism, particularly during adenosine triphosphate (ATP) generation from glucose, is a significant source of ROS. These highly reactive molecules can cause oxidative damage to various cellular components, including nucleic acids, proteins, and lipids, leading to functional impairments and contributing to the aging process.

The generation of ROS is influenced by both intrinsic and extrinsic factors. Intrinsically, ROS are produced as byproducts of normal cellular metabolic processes, particularly within the mitochondria. Mitochondrial dysfunction, a hallmark of aging, can exacerbate ROS production, leading to an imbalance in the redox state of the cell. This imbalance, termed oxidative stress, results when the production of ROS exceeds the capacity of the cellular antioxidant defenses to neutralize them, thus causing damage to cellular structures and signaling pathways [22].

Extrinsically, environmental factors such as ultraviolet radiation, pollution, and unhealthy lifestyle choices (e.g., smoking and poor nutrition) can also increase ROS levels. These external stressors can disrupt the redox equilibrium, further contributing to oxidative stress and its associated cellular damage [22].

As aging progresses, the accumulation of oxidative damage from ROS leads to various deleterious effects, including cellular senescence, inflammation, and an increased risk of age-related diseases such as cardiovascular diseases, neurodegenerative disorders, and cancer [23]. The role of oxidative stress in the aging process is underscored by its involvement in cellular senescence, which manifests as a reduced capacity of cells to proliferate and respond to damage [24].

Furthermore, the relationship between oxidative stress and aging is not merely one of damage; it also involves complex signaling pathways. For instance, the p66Shc protein has been identified as a key regulator of ROS levels and has been implicated in aging and longevity. Its phosphorylation on serine 36 is crucial for the initiation of cell death under oxidative stress conditions, highlighting the dual role of ROS in both damaging and signaling capacities within cells [24].

In summary, cellular metabolism regulates aging through the generation of ROS, which can lead to oxidative stress when not adequately managed by antioxidant defenses. This oxidative stress contributes to cellular damage and dysfunction, ultimately influencing the aging process and the onset of age-related diseases. Understanding the intricate balance between ROS production and antioxidant defenses is essential for developing strategies aimed at promoting healthy aging and mitigating the effects of oxidative stress.

5.2 Antioxidant Defense Mechanisms ​

Cellular metabolism plays a crucial role in regulating aging through various mechanisms, particularly by influencing oxidative stress and the body's antioxidant defense systems. Aging is characterized by a gradual decline in physiological functions, which is closely associated with metabolic changes that affect cellular health and longevity.

Oxidative stress, defined as an imbalance between pro-oxidants and antioxidants, significantly contributes to the aging process. It leads to the accumulation of damage to DNA, proteins, and lipids, ultimately driving the pathogenesis of age-related diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is vital for maintaining cellular redox homeostasis. In younger organisms, Nrf2 mediates the antioxidant response, promoting a youthful cellular phenotype by regulating the transcription of cytoprotective genes. However, aging impairs Nrf2 signaling, which results in increased oxidative stress and cellular senescence, further exacerbating age-related pathologies, particularly in the vascular system[25].

The relationship between metabolism and oxidative stress is further complicated by the role of p53, a key regulator of cellular responses to oxidative stress. p53 exhibits context-dependent activities; it can function as an antioxidant at low levels of oxidative stress to ensure cell survival, but at high levels, it may promote pro-oxidative activities that lead to cell death. This dual role of p53 highlights the importance of metabolic conditions in determining cellular fate during aging[26].

Antioxidants play a critical role in counteracting oxidative stress and improving longevity. Research indicates that antioxidant molecules can mitigate oxidative damage by interrupting free radical propagation or inhibiting free radical formation. These actions not only reduce oxidative stress but also enhance immune function, contributing to healthier aging[27]. Moreover, dietary factors, including calorie restriction and specific nutrients, can influence antioxidant defense mechanisms, thus modulating the aging process. For instance, glucose metabolism has been implicated in aging; impaired glucose metabolism may extend life expectancy by regulating autophagy and oxidative stress levels[28].

In summary, cellular metabolism regulates aging through its intricate relationship with oxidative stress and antioxidant defense mechanisms. The balance of metabolic pathways, oxidative stress responses, and the activity of key regulatory proteins such as p53 and Nrf2 are essential for maintaining cellular integrity and promoting longevity. Understanding these mechanisms provides potential therapeutic avenues for mitigating age-related decline and enhancing healthspan.

6 Therapeutic Interventions Targeting Metabolism ​

6.1 Caloric Restriction and Fasting ​

Cellular metabolism plays a crucial role in regulating aging through various mechanisms that impact cellular function, tissue homeostasis, and overall health. As organisms age, metabolic alterations can lead to impaired cellular function and contribute to the aging process. One significant aspect of metabolic regulation in aging is the relationship between metabolism and inflammation, often referred to as "inflammaging." This chronic, low-grade inflammation is driven by metabolic dysregulation in immune cells, which affects their functionality and contributes to age-related diseases (Bevilacqua et al. 2023; Ginefra et al. 2024).

In the context of therapeutic interventions, caloric restriction and fasting have emerged as powerful strategies for modulating metabolism and potentially extending lifespan. These interventions are known to induce metabolic reprogramming, leading to improved cellular stress responses, enhanced autophagy, and reduced oxidative stress. For instance, caloric restriction has been shown to promote metabolic flexibility, allowing cells to adapt to varying nutrient availability, which is essential for maintaining tissue homeostasis and promoting longevity (Wei et al. 2025; Raza 2024).

Caloric restriction and fasting exert their effects through several pathways. They can activate sirtuins, a family of proteins that regulate cellular health and longevity by influencing metabolic pathways and promoting mitochondrial function. Sirtuins are involved in the deacetylation of various substrates, including histones and non-histone proteins, which can lead to changes in gene expression that favor longevity (Brunet & Rando 2017). Additionally, these interventions can enhance the production of ketone bodies during fasting, which serve as alternative energy sources and have been associated with anti-inflammatory effects (Chiang et al. 2025).

Furthermore, caloric restriction and fasting have been linked to improved insulin sensitivity and reduced inflammation, both of which are crucial for counteracting age-related metabolic decline (Lien et al. 2025). By promoting a state of metabolic health, these interventions may help to mitigate the effects of aging on immune function, thereby enhancing resilience against age-related diseases (Saleh et al. 2024).

In conclusion, cellular metabolism is intricately linked to the aging process, with metabolic dysregulation contributing to age-related decline in function. Therapeutic interventions such as caloric restriction and fasting offer promising avenues for enhancing metabolic health, potentially delaying the onset of age-related diseases and promoting longevity through their multifaceted effects on cellular metabolism and inflammation. Future research should continue to explore the underlying mechanisms of these interventions to optimize strategies for healthy aging and longevity.

6.2 Pharmacological Agents and Metabolic Modulators ​

Cellular metabolism plays a pivotal role in regulating aging by influencing various cellular processes, including energy production, signaling pathways, and the maintenance of cellular homeostasis. Metabolic alterations associated with aging contribute to the decline in tissue function and regenerative capacity, impacting overall health and longevity. Understanding these metabolic changes opens avenues for therapeutic interventions aimed at mitigating the effects of aging.

Aging is characterized by a decline in cellular metabolic function across various tissues, leading to dysfunction in multiple organ systems. For instance, the aging process affects stem cells, which are essential for tissue homeostasis and regeneration. Aged stem cells exhibit diminished proliferative capacity and differentiation potential, compromising tissue regeneration and contributing to age-related disorders (Wei et al. 2025). This decline is often associated with metabolic plasticity, where stem cells must adapt their energy requirements during self-renewal and differentiation. Emerging evidence suggests that the interaction between metabolic pathways and epigenetic modifications is crucial for regulating stem cell fate decisions (Wei et al. 2025).

In T cells, aging induces significant metabolic reprogramming that contributes to "inflammaging," a chronic low-grade inflammatory state associated with aging. Memory CD4+ T cells from aged individuals demonstrate increased mitochondrial content and reactive oxygen species (ROS) production, leading to elevated expression of proinflammatory cytokines. This metabolic shift not only impairs T cell function but also exacerbates age-related inflammation, which can accelerate the aging process itself (Chen et al. 2022). Moreover, metabolic alterations in T cells have been linked to poor clinical outcomes in age-related diseases, emphasizing the need for interventions that target these metabolic pathways to enhance immune function in the elderly (Han et al. 2023).

Pharmacological agents and metabolic modulators are emerging as potential therapeutic strategies to counteract age-related metabolic decline. For example, interventions that target the mechanistic target of rapamycin (mTOR) pathway have shown promise in enhancing metabolic health and promoting longevity. mTOR inhibitors can improve cellular metabolism and reduce the senescence of various cell types, including stem cells and immune cells (Martin et al. 2021). Additionally, the manipulation of nutrient-sensing pathways and the regulation of autophagy are being explored as strategies to rejuvenate aged cells and restore metabolic function (Raza 2024).

Furthermore, the modulation of metabolic pathways using specific compounds may offer novel therapeutic avenues. For instance, compounds that enhance mitochondrial function or modulate the NAD+/NADH ratio can improve metabolic efficiency and reduce oxidative stress in aged cells, potentially reversing some aspects of metabolic aging (Lien et al. 2025). The development of such pharmacological agents could provide a multifaceted approach to mitigate the effects of aging by targeting the underlying metabolic dysfunctions.

In conclusion, cellular metabolism significantly regulates aging through its impact on various biological processes, including stem cell function, immune response, and tissue homeostasis. Therapeutic interventions that target metabolic pathways, such as pharmacological agents and metabolic modulators, hold promise for enhancing healthspan and mitigating the effects of aging. Future research should focus on elucidating the intricate relationships between metabolism and aging to develop effective strategies for promoting longevity and improving the quality of life in aging populations.

7 Conclusion ​

This review highlights the significant role of cellular metabolism in regulating aging, emphasizing the intricate connections between metabolic pathways and age-related physiological decline. Key findings indicate that metabolic reprogramming in various cell types, including immune cells and stem cells, is a hallmark of aging, leading to chronic inflammation and impaired regenerative capacity. The decline in mitochondrial function and the dysregulation of nutrient-sensing pathways, such as insulin/IGF-1 and mTOR, further exacerbate the aging process by increasing oxidative stress and promoting cellular senescence. Importantly, therapeutic interventions such as caloric restriction, fasting, and pharmacological agents targeting metabolic pathways have shown promise in mitigating the effects of aging and enhancing healthspan. Future research should focus on unraveling the complex mechanisms underlying metabolic alterations in aging, aiming to develop effective strategies for promoting longevity and improving the quality of life in an increasingly aging population. The potential for targeting metabolic pathways as a therapeutic approach to extend healthspan and longevity underscores the importance of this field in addressing age-related challenges.

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