SIRT1 Activators as Geroprotective Agents in Brain Aging: Mechanisms and Therapeutic Potential

Aging is a multifactorial process that affects different tissues and organs, including the brain, and is influenced by genetic and environmental factors (Cai et al., 2022). The primary processes related to aging are progressive accumulation of inflammatory molecules, chronic inflammation, and the development of aberrant cellular signaling (Chung et al., 2019). During human life, the cellular system is frequently exposed to external genotoxic factors, such as chemical and physical agents, and internal genotoxic factors, which increase the risk of DNA injury and mutagenesis and dysregulate the neuroprotective silencing information regulator 2-related enzyme 1 (SIRT1) (Rosendahl Huber et al., 2021). SIRT1 is strongly downregulated during brain aging, leading to increased cellular senescence (Sung et al., 2021). Therefore, increasing brain SIRT1 signaling can attenuate the development and progression of brain aging.

On the other hand, geroprotectors, which inhibit aging and extend lifespan, have been increasingly suggested to play a critical role in aging by modulating the SIRT1 signaling pathway (Morsli & Bellantuono, 2021). Notably, SIRT1 activation acts as an anti-aging mechanism by modulating the SIRT1/acetyl-NF-κB signaling axis and stimulating autophagy (Morsli & Bellantuono, 2021). Accordingly, this review highlights the potential protective role of SIRT1 and the geroprotective effects of SIRT1 activators in brain aging. The therapeutic potential of SIRT1 activators is supported by different preclinical and early clinical studies, suggesting their value in preventing or delaying brain aging. Thus, SIRT1 could be a promising pharmacological target for age-associated brain disorders, warranting more robust translational studies to validate these findings in humans. Therefore, this narrative review aims to discuss, explain, and critically evaluate the emerging evidence for SIRT1 activators that modulate various cellular and molecular signaling pathways in brain aging.

SIRT1 is an NAD⁺-dependent deacetylase involved in regulating cellular senescence, aging, and other cellular and molecular processes (Table 1). SIRT1 plays a critical role in genomic stability during aging and regulates aging and cellular senescence (Chen et al., 2020). The expression of SIRT1 declines with aging, though increased SIRT1 expression is sufficient to extend lifespan in yeast and mice (Chen et al., 2020). Notably, SIRT1 regulates gene expression by deacetylating acetyl-lysine residues on both histone and non-histone substrates. SIRT1 also interacts with proteins in multiple signaling pathways, thereby influencing a wide range of biological, physiological, and pathological processes (Cui et al., 2022). For instance, SIRT1 suppresses the release of inflammatory mediators by downregulating NF-κB expression, thereby mitigating toxicant-induced inflammatory damage (Cui et al., 2022). Although the mechanism of SIRT1-activating compounds (STACs) remains debated, evidence suggests that specific hydrophobic motifs in SIRT1 substrates, such as peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) and FOXO3a, enhance SIRT1 activation (Hubbard et al., 2013). A single amino acid, Glu230, located in the structured N-terminal domain of SIRT1, is essential for activation by both conventional STAC scaffolds and newer chemically distinct activators. Notably, in primary cells expressing activation-deficient SIRT1, the metabolic effects of STACs are abolished (Hubbard et al., 2013). Furthermore, SIRT1 is involved in aging and longevity by modulating signaling pathways, such as PGC-1α, which promotes mitochondrial biogenesis. SIRT1 is located in the nucleus and can deacetylate transcription factors and histone enzymes, including histone methyltransferases (Yang et al., 2022).

Interestingly, SIRT1 promotes apoptotic cell death and improves protein stability by regulating insulin-like growth factor 1 (IGF-1) and PI3K (Batiha et al., 2023; Xu et al., 2020; Yang et al., 2022). Importantly, caloric restriction is regarded as a key mechanistic pathway for SIRT1 activation, leading to PGC-1α and histone activation, and to the suppression of p53 and NF-κB (Batiha et al., 2023; Xu et al., 2020; Yang et al., 2022). These integrated mechanisms are summarized in Fig. 1. Although there is considerable interest in enhancing SIRT1 catalytic activity, its regulation at the protein level remains poorly understood. Evidence indicates that macroautophagy, a catabolic pathway involving autophagosomes and lysosomes, drives the downregulation of mammalian SIRT1 during cellular senescence and aging (Xu et al., 2020). In senescent cells, nuclear SIRT1 is an autophagy substrate and degraded through cytoplasmic autophagosome-lysosome activity mediated by the autophagy protein LC3. This autophagy-lysosome pathway has been shown to contribute to the decline of SIRT1 in aging tissues (Xu et al., 2020). Therefore, modulating autophagy may represent a potential approach to stabilize SIRT1 and support healthy aging. Such effects could reduce inflammation and apoptosis, enhance genomic stability and mitochondrial biogenesis, and ultimately promote longevity.

Also, SIRT1 increases antioxidant expression, resulting in a significant reduction in oxidative stress and inhibition of inflammatory responses in aging (Al-Kuraishy et al., 2023; Yang et al., 2022). SIRT1 affects numerous biological processes by deacetylating diverse proteins involved in inflammation. Evidence suggests that SIRT1 is downregulated during the acute inflammatory response and related diseases, both in vivo and in vitro (Yang et al., 2022; Zhang et al., 2010). Conversely, while SIRT1 significantly reduced the inflammatory reactions to IL-1β and TNF-α in human dermal microvascular endothelial cells (HDMEC), no significant change in SIRT1 expression was observed in psoriatic HDMEC treated with IL-1β, IFN-γ, and IL-17 (Orecchia et al., 2011). Interestingly, both NF-κB and oxidative stress, which are elevated with aging, inhibit SIRT1 expression (Cui et al., 2022). However, optimal levels of ROS and nitrogen oxidative species (NOS) are necessary for cellular molecular signaling (Ivanova & Lyublinskaya, 2021), and excessive use of antioxidants can induce redox imbalance, leading to a harmful condition called antioxidant stress (Ge et al., 2022). Therefore, SIRT1, which regulates oxidative stress and antioxidant balance, appears to be a more appropriate signaling pathway for preventing aging and is considered a geroprotector.

The frequency of DNA damage increases with age, leading to genomic instability and an increased risk of mutations (Wang et al., 2021). Genome instability has long been implicated as the primary causal factor in aging. Somatic cells are continuously exposed to various sources of DNA damage, from ROS to UV radiation to environmental mutagens. However, DNA repair is erroneous, and such defects, as well as the occasional failure to correctly replicate the genome during cell division, are the basis for mutations and epimutations (Wang et al., 2021). There is now ample evidence that mutations accumulate in various organs and tissues of humans and animals. What is not known, however, is whether the frequency of these random changes is sufficient to cause the phenotypic effects generally associated with aging (Wang et al., 2021). Therefore, somatic tissues of aging organs have normal and mutant cells forming mosaicism (Vijg & Dong, 2020) (Figure 2).

Of note, mechanisms such as DNA repair and the elimination of injured cells through apoptosis reduce DNA damage and the accumulation of mutant cells (Poetsch, 2020). However, these protective mechanisms are impaired during aging. Paradoxically, DNA repair is subjected to age-related changes and deterioration. For example, the efficiency of mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER), and double-strand break (DSB) repair systems is impaired, leading to DNA mutations during aging (Gorbunova et al., 2007). Interestingly, endogenous antioxidants are the primary mechanism for reducing cell injury and macromolecular damage (Mumtaz et al., 2021). Depletion of endogenous antioxidant capacity and SIRT1 during aging promotes the development of oxidative stress, which triggers oxidative modifications of DNA and other macromolecules, resulting in various pathological processes such as neurodegeneration and carcinogenesis (Mumtaz et al., 2021). Therefore, the intensification of antioxidant defense mechanisms, the promotion of DNA repair, the elimination of dysfunctional aged cells (senescent cells), and the activation of the SIRT1 signaling pathway could be potential mechanisms for longevity (Wichansawakun & Buttar, 2019) (Figure 3).

In this context, agents that attenuate the development and progression of the aging process are called geroprotectors, which are senotherapeutics that affect the root causes of aging and related disorders by targeting senescent cells (Mbara et al., 2022). Senotherapeutics are commonly classified as senostatic (senomorphic), which inhibit the senescence-associated secretory phenotype (SASP), and senolytics, which trigger the death of senescent cells (Zhang et al., 2023). SASP is a group of molecules, including chemokines, pro-inflammatory cytokines, proteases, inhibitory molecules, bioactive lipids, extracellular vesicles, and other metabolites that induce chronic inflammation and cellular dysfunction (Kumari & Jat, 2021). In this context, SIRT1 may reduce aging and age-related disorders by inhibiting SASP expression (Zhang et al., 2023). SASP components affect surrounding cells and alter their microenvironment; SASP may be a key mechanism linking cellular senescence to individual aging and age-related diseases. Findings from a preclinical study showed that SIRT1 negatively regulated SASP factor expression at the transcriptional level during cellular senescence (Zhang et al., 2023), suggesting that SIRT1 repressed SASP factor expression by deacetylating histones at their promoter regions. Cellular senescence is activated by numerous stressors mediated by the aging process. Upon SASP release, senescent cells can modulate apoptosis and survival pathways (Schulz, 2023).

In normal tissues, proliferation of precursor cells is balanced by terminal differentiation and cell loss. Replicative senescence occurs after cells have undergone many replicative cycles or, more rapidly, in response to inappropriate proliferation signals. It is induced by TP53, specific cell cycle inhibitors, and RB1 (Schulz, 2023). Various forms of cell death, like apoptosis, can be elicited by stress, damage, inappropriate proliferation, or cytotoxic immune cells. Apoptosis can be initiated by two pathways that converge into a common execution cascade. The intrinsic pathway triggers the mitochondrial permeability transition, which ultimately leads to the activation of executor caspases. The extrinsic pathway is initiated by death receptors activated by cytokine ligands or cytotoxic immune cells; it can engage the intrinsic pathway for support. Diverse BH3 proteins stimulate, inhibit, or conduct apoptosis. Insufficient apoptosis in aged cells can result from inactivation of death receptor signaling, downregulation of pro-apoptotic factors, or upregulation of anti-apoptotic factors, driven by genetic or epigenetic alterations. Apoptotic ability is moreover compromised by TP53 inactivation or activation of PI3K and NFκB signaling (Schulz, 2023).

Moreover, senescent cells upregulate anti-apoptotic pathways, preventing them from dying despite the accumulation of damaged organelles and DNA. Therefore, cellular senescence may be a therapeutic target for aging and lifespan extension. However, senomorphics, such as NF-κB inhibitors, suppress senescent cells by inhibiting SASP. Nonetheless, senolytic agents promote apoptosis by targeting critical enzymes involved in pro-survival and pro-apoptotic signaling, such as p53 (Lagoumtzi & Chondrogianni, 2021). In addition, senotherapeutics may act as senolytic and senomorphic (Lagoumtzi & Chondrogianni, 2021). Senescent cells generally display heightened resistance to apoptotic signals. The development of first-generation senolytic agents was guided by hypothesis-driven, mechanism-based strategies that focused on disrupting anti-apoptotic pathways. Apoptosis is regulated by multiple factors, including B-cell lymphoma 2 (BCL-2) family proteins, heat shock proteins, and signaling pathways such as p53 and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt). The senolytics ABT-737 and ABT-263 promote apoptosis in senescent cells by inhibiting BCL-2 family proteins (Lagoumtzi & Chondrogianni, 2021). Furthermore, natural flavonoids such as quercetin and fisetin function as senolytics by suppressing the PI3K/Akt survival pathway, whereas dasatinib exerts senolytic activity by targeting Src/tyrosine kinases (Wang et al., 2022). In particular, the combination of dasatinib and quercetin has been shown to eliminate p21-overexpressing cells in visceral adipose tissue (VAT) of obese individuals. In transplantation studies, mice receiving vehicle-treated human VAT developed glucose intolerance and insulin resistance. In contrast, those transplanted with VAT treated with dasatinib and quercetin remained insulin-sensitive and showed improvements in adverse metabolic outcomes (Wang et al., 2022). Moving to second-generation senolytics, these compounds are designed to target senescence-associated β-galactosidase (SA-β-gal), an enzyme that accumulates in senescent cells. For instance, the agent KSL0608-Se becomes phototoxic in the presence of SA-β-gal and selectively eradicates senescent cells in a light-dependent, dose-responsive manner (Shi et al., 2023).

It has been shown that during aging, SIRT1 levels are generally reduced, leading to increased oxidative stress; however, low levels of oxidative stress can even extend lifespan (Salminen et al., 2013). SIRT1 can stimulate antioxidant gene expression via the FoxO pathways and inhibit NF-κB signaling, a significant inducer of inflammatory responses. Remarkably, an increased level of ROS can both directly and indirectly control the activity of the SIRT1 enzyme. For instance, ROS can inhibit SIRT1 activity by evoking oxidative modifications on its cysteine residues. Decreased SIRT1 activity enhances NF-κB signaling, which supports inflammatory responses. This crosstalk between SIRT1 and ROS signaling provokes, in a context-dependent manner, a decline in autophagy and a low-grade inflammatory phenotype, both common hallmarks of ageing (Salminen et al., 2013).

Preclinical studies have shown a progressive decline in SIRT1 expression in the brains of aged mice (Diaz-Perdigon et al., 2020). Since epigenetic changes are key contributors to aging, SIRT1, like SIRT2, may counteract age-related cognitive decline and neuropathology, as demonstrated in SAMP8 mice (Diaz-Perdigon et al., 2020). The age-related reduction of SIRT1 is even more pronounced in models of accelerated aging (Sasaki et al., 2006). In prematurely senescent cells, SIRT1 decreases rapidly and shows an inverse correlation with SA-β-gal activity. Both in mouse and human fibroblasts, SIRT1 expression is positively correlated with proliferating cell nuclear antigen (PCNA), a DNA replication factor expressed during S-phase (Sasaki et al., 2006). In animals, age-related declines in SIRT1 are most evident in tissues with reduced mitotic activity, such as the thymus and testes, but not in tissues like the brain, where mitotic activity remains relatively stable (Sasaki et al., 2006). These reductions in SIRT1 closely parallel decreases in PCNA levels. Interestingly, while SIRT1 loss is accelerated in mice with premature aging, it is absent in long-lived growth hormone receptor knockout mice (Sasaki et al., 2006). Therefore, as mitotic activity ceases in mouse and human cells in the typical environment of the animal or the culture dish, SIRT1 levels decline concomitantly. Aging-induced SIRT1 loss is tissue-specific; it is gradually reduced in the brain (Gong et al., 2014). Therefore, different life stages, including young age before maturation, adulthood, middle age, and old age, are associated with SIRT1 expression, which declines with age at the transcriptional and translational levels in the brain, liver, skeletal muscle, and white adipose tissue in SAM-P8 and SAM-R1. SIRT1 expression is lower in SAM-P8 than in SAM-R1, particularly at old age (Gong et al., 2014). A prospective cohort study in men aged 70 years and older found that serum-induced SIRT1 expression was not associated with age or mortality. Instead, it correlated with markers of body composition and nutritional status, including height, weight, body fat percentage, lean mass, albumin, and cholesterol, but showed no association with disease (Razi et al., 2017). Similarly, SIRT1 SNPs rs2273773, rs3740051, and rs3758391 were not associated with age, frailty, or mortality, but were associated with weight, height, body fat, lean mass, and albumin levels. No relationship was observed between these SNPs and serum-induced SIRT1 expression (Razi et al., 2017). Therefore, SIRT1 and serum-induced SIRT1 protein levels are mainly associated with nutritional status rather than aging. In addition, SIRT1 activity reflects metabolic status rather than the aging process (Lee & Yang, 2017).

Correlation analysis of the retrospective study showed that SIRT1 activity is significantly correlated with serum triglyceride levels in men and with waist circumference, systolic blood pressure, diastolic blood pressure, and serum triglyceride levels in women. Positive correlation was observed between SIRT1 activity and BMR in women but not in men (Lee & Yang, 2017), suggesting that serum SIRT1 activity may be a biomarker of aging. In addition, a positive correlation between SIRT1 activity and BMR in women indicates that serum SIRT1 activity may reflect energy expenditure well in humans. These findings highlight the sex-related effect of SIRT1. Conversely, a cohort study found that SIRT1 levels are elevated with age, particularly in subjects with the SIRT1 rs7895833 polymorphism, suggesting a compensatory role for SIRT1 in mitigating age-related oxidative stress (Woźny et al., 2017). A clinical finding revealed that SIRT1 expression is reduced in elderly patients with chronic heart failure due to upregulation of pro-apoptotic p53 (Lu et al., 2014). Thus, in advanced heart failure, reduced SIRT1 expression, similar to age-related changes, may contribute significantly to decreased antioxidant activity and increased expression of pro-apoptotic molecules via the p53, FoxO1, and oxidative stress pathways (Lu et al., 2014). These observations underscore the decline in SIRT1 signaling as a hallmark of the aging process.

Brain function progressively deteriorates with aging due to functional and structural neuronal changes, including morphological changes in dendritic spines and dysfunction of synaptic plasticity/neurotransmission (Melo Dos Santos et al., 2024). Brain aging manifests in cognitive impairment, memory disorders, attention deficit, and visuospatial disorientation (Habes et al., 2021). Neuronal senescence is the primary pathway in the progression of brain aging (Sahu et al., 2022). Remarkably, senescence neurons have a low capacity to undergo apoptosis, exhibit impaired autophagy, yet show augmented SAβ-gal activity (Kavanagh et al., 2021; Sah et al., 2021). Cellular senescence is now understood as a multifaceted stress response that alters cell fate. Rather than responding to cellular or DNA damage with proliferation or apoptosis, senescent cells persist in a permanent state of cell cycle arrest. These cells also contribute to chronic tissue decline by releasing harmful factors that negatively influence neighboring cells (Sah et al., 2021). In neuroscience, the concept of senescence has been extended to the brain, even to post-mitotic cells, a notion that initially posed challenges for senescence researchers. Nevertheless, growing investigations into the role of senescence in brain aging, neurodegenerative diseases, and injury are driving progress in this field (Sah et al., 2021).

It has been shown that biomarkers of the senescent cells are increased during brain aging (Kavanagh et al., 2021). For example, circulating plasminogen activator inhibitor-1 (PAI-1), the only inflammation-related biomarker found to increase with age, is considered an indicator of senescent cell burden (Kavanagh et al., 2021). Findings from a preclinical study revealed that PAI-1, a serine protease inhibitor, is upregulated and correlates with increased expression of cell cycle repressors p53 and p21 in the hippocampus/cortex of senescence-accelerated mouse prone 8 (SAMP8) mice and AD patients. Double immunostaining results show that astrocytes in the brains of AD patients and SAMP8 mice express higher levels of senescent markers and PAI-1 than those in the corresponding controls (Kavanagh et al., 2021), suggesting that increased PAI-1 may contribute to brain cell senescence in AD. Senescent astrocytes can induce neuron apoptosis through secreting pathologically active molecules, including PAI-1. Moreover, extensive evaluation of adipose SAβ-gal staining in a relevant animal model of human aging supports the validity of PAI-1as a biomarker of age-associated processes (Kavanagh et al., 2021).

Remarkably, neuronal senescent cells resist apoptosis and depend mainly on autophagy for their metabolic functions. The heterogeneity of senescent cells indicates that they rely on different proteins or pathways for survival. Therefore, a better understanding of the underlying mechanisms for apoptotic resistance of senescent cells will provide new molecular targets for the development of cell-specific or broad-spectrum therapeutics to clear senescent cells (Hu et al., 2022). As the brain ages, its functional capacity progressively declines, and cellular senescence contributes to aging and is a hallmark of many age-related conditions. The transcriptional repressor known as RE1-silencing transcription factor (REST) has been linked to aging and plays a crucial role in protecting neurons from developing a senescent phenotype (Rocchi et al., 2021). Loss of REST function disrupts autophagy and proteostasis, elevates oxidative stress, and increases neuronal death. Thus, restoring autophagy function can counteract key features of senescence (Rocchi et al., 2021). Therefore, REST contributes to healthy brain aging by maintaining autophagic activity and regulating the senescence program in neurons, processes relevant to neurodegenerative disorders associated with aging. Healthy brain aging involves a combination of physical activity, good nutrition, staying mentally and socially engaged, managing health conditions (e.g., blood pressure, diabetes), getting enough quality sleep, and avoiding processed foods to slow cognitive decline and maintain function, distinguishing regular, subtle changes from dementia (Gronek & Tang, 2023). Conversely, unhealthy brain aging involves accelerated cognitive decline beyond regular changes, characterized by faster processing, significant memory loss, difficulties with problem-solving, and behavioral issues, often linked to lifestyle factors like poor diet, lack of sleep, stress, inactivity, and vascular problems that increase risk for neurodegenerative diseases. Unhealthy aging is characterized by more severe declines due to factors such as white matter lesions, protein buildup (amyloid), and reduced neurotransmitter levels, accelerating disease risk (Peter et al., 2025) (Figure 4).

Furthermore, glial cells tend to undergo senescence, leading to increased release of pro-inflammatory cytokines and the development of neuroinflammation. Senescent glial cells exacerbate neuroinflammation, disrupt synaptic function, and promote neuronal death (Alshaebi et al., 2025). Indeed, age-related memory and cognitive impairment are associated with brain changes, particularly in the hippocampus and prefrontal cortex (Jobson et al., 2021). These neuropathological alterations increase the risk of developing neurodegenerative disorders (Jobson et al., 2021; Zhang et al., 2019). It has been shown that gene expression of brain neurotransmitters and neuronal proteins required for synaptic plasticity and cognitive function is reduced after 40 years, leading to cognitive impairments (Aquilani et al., 2023). The hallmarks for neuronal aging are impairment of the clearance system, accumulation of oxidized proteins, reduction of neuronal energy metabolism, and abnormal adaptive stress response (Błaszczyk, 2020). Also, alterations in synaptic neurotransmission and the development of aberrant synaptic function are commonly recognized in the aged brain (Nagy et al., 2021). Moreover, the neuroprotective polyamine spermidine, which improves synaptic plasticity and has anti-aging effects, is highly reduced in the aging brain (Chen et al., 2020).

SIRT1, the well-studied mammalian sirtuin, functions across various tissues and organs, but its influence on aging and lifespan is particularly linked to its role in CNS neurons (Batiha et al., 2023; Yang et al., 2022). SIRT1 regulates energy metabolism, circadian rhythm, supports dendritic and axonal growth, and enhances neuronal resilience to stress. SIRT1 is also essential for maintaining plasticity, cognitive performance, and protection against age-related neurodegeneration and cognitive decline (Batiha et al., 2023; Yang et al., 2022). Furthermore, SIRT1 plays a critical role in regulating brain function. It has a neuroprotective effect against brain aging and neurodegenerative diseases by activating neurogenesis and modulating neuritogenesis, the outgrowth of axons and dendrites (Herskovits & Guarente, 2014). Herskovits and Guarente found that SIRT1 is necessary for brain development and control of brain senescence (Herskovits & Guarente, 2014). SIRT1 promotes axonal growth, dendritic branching, and neurite outgrowth, and enhances memory function by activating synaptic plasticity (Herskovits & Guarente, 2014).

In the human brain, SIRT1 is abundantly expressed and contributes to enhanced neurogenesis and neuronal myelination (Mormone et al., 2023). It plays a pivotal role in axonal development and dendritic function, supporting synaptic plasticity and cognitive performance while protecting against age-related neurodegeneration and cognitive decline (Godoy et al., 2014; Ng et al., 2015). Notably, SIRT1 mRNA is abundantly expressed in brain regions that regulate energy balance and metabolic activity, such as the hypothalamus, the nucleus tractus solitarius, and pro-opiomelanocortin (POMC) neurons (Ramadori et al., 2008). However, SIRT1 protein levels specifically rise in the hypothalamus during fasting, a response that is disrupted in leptin-deficient obese mice (Ramadori et al., 2008). Beyond the metabolically relevant regions, SIRT1 mRNA is also abundantly expressed in the piriform cortex, hippocampus, medial habenular nucleus, and cerebellum (Ramadori et al., 2008).

Remarkably, activation of the hippocampal SIRT1 signaling pathway improves cognitive function in transgenic mice by enhancing proteostasis and activating neurotrophic factors (Corpas et al., 2017). Likewise, the SIRT1 signaling pathway is an essential protective pathway against hippocampal atrophy and the cognitive impairment it induces during aging (Sun et al., 2022). Therefore, they may be potential therapeutic targets for preventing and intervening in aging-related neurodegenerative diseases. SIRT1 acts as a central NAD⁺-dependent metabolic sensor that integrates multiple signaling pathways involved in brain aging. Age-related decline in NAD⁺ availability reduces SIRT1 activity, contributing to mitochondrial dysfunction, impaired antioxidant defense, and chronic neuroinflammation. In neurons, SIRT1 regulates mitochondrial biogenesis, synaptic plasticity, and survival signaling through pathways such as AMPK/PGC-1α and Akt/mTOR.

In contrast, in glial cells, particularly microglia, SIRT1 primarily modulates neuroinflammatory responses by suppressing NF-κB-mediated transcription of pro-inflammatory cytokines. Therefore, the NAD⁺–SIRT1 axis represents a unifying mechanistic framework linking metabolic regulation, inflammatory signaling, and neuronal resilience during brain aging. SIRT1 modulates inflammatory responses by deacetylating histones and critical transcription factors, such as activator protein 1 and NF-κB, thereby blocking the transcription of specific genes that promote inflammation. SIRT1 also supports vascular endothelial cells by regulating antioxidant genes via a FoxO3a/PGC-1α complex (Cao et al., 2018). Evidence supports SIRT1’s involvement in aging and its interactions with several signaling pathways, including NF-κB, AMPK, mTOR, p53, PGC1α, and FoxOs (Chen et al., 2020). Notably, SIRT1 regulates several processes, including the inflammatory response, apoptosis, oxidative stress, energy metabolism, and autophagy, through deacetylase activity and NF-κB signaling. As the center of multiple intracellular signaling pathways, NF-κB activity is regulated by multiple factors. SIRT1 can both directly deacetylate NF-κB and, indirectly through other molecules, inhibit its activity (Liu et al., 2024). Findings from preclinical study illustrated that ginsenoside Rg3 is effective in reducing neuroinflammation and damage in hippocampal neurons subsequent traumatic brain injury by modulating the SIRT1/NF-kB pathway signifying its possible as a therapeutic agent for traumatic brain injury (Liu et al., 2024). The SIRT1/NF-kB pathway is crucial in the regulation of brain injury and it has been shown that certain medications can mitigate brain injury by activating SIRT1 and deactivating NF-kB (Song & Zhou, 2022). Moreover, SIRT1 regulates the expression of several antioxidant genes such as superoxide dismutase, catalase, peroxiredoxins 3 and 5 (Prx3, Prx5), thioredoxin 2 (Trx2), thioredoxin reductase 2 (TR2), and uncoupling protein 2 (UCP-2) by upregulating the FoxO3a/PGC-1α complex (Olmos et al., 2013). Gupta et al. illustrated that FOXO transcription factors, regulated by SIRT1 deacetylation, enhance antioxidant defense mechanisms, thereby counteracting oxidative stress and metabolic dysregulation in brain aging. Moreover, key redox-sensitive regulators such as Nrf2 and PGC-1α interact with this pathway, arranging mitochondrial biogenesis and adaptive stress responses (Gupta et al., 2025). In addition, the longevity-related AMPK/SIRT1/PGC-1α signaling pathway and brain IGF1/PI3K/Akt survival pathway are significantly reduced in brain aging, and increased after exercise training in animal models signifying that exercise not only reduced aging-induced brain apoptosis and inflammatory signaling activity, but also enhanced the survival pathways in the hippocampus, which provides one of the new beneficial effects for exercise training in aging brain (Lin et al., 2020). Primary neurons derived from transgenic mice overexpressing SIRT1 exhibit greater neurite outgrowth and survival, primarily due to the negative regulation of mammalian/mechanistic target of rapamycin (mTOR) signaling. SIRT1 localizes at the axonal growth cone, where its activation promotes axon formation and elongation, likely through AKT deacetylation (Li et al., 2013).

Furthermore, SIRT1 has neuroprotective effects against the development and progression of neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) (Batiha et al., 2023). AD is the most common neurodegenerative disease due to the progressive accumulation of Aβ and hyperphosphorylated tau protein. AD is an age-related disease characterized by cognitive impairment and memory loss (Al-Kuraishy et al. 2025a, b). Senolytic therapy in AD mouse models has been shown to selectively eliminate senescent cells from the plaque microenvironment, leading to reduced neuroinflammation, decreased Aβ burden, and improvements in cognitive performance (Zhang et al., 2019). Preclinical evidence further indicates that senescent cells progressively accumulate with age across multiple organ systems (Zhang et al., 2019). In the brain, tau protein aggregation is strongly linked to cognitive deterioration in AD and other tauopathies, and it appears to drive cellular senescence (Al-Kuraishy et al. 2025a, b). Pharmacological removal of senescent cells in tauopathy mouse models alleviates disease pathology. Compared with vehicle-treated controls, mice given intermittent senolytic treatment showed reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, normalized cerebral blood flow, and diminished ventricular enlargement. Importantly, intermittent administration of dasatinib plus quercetin has demonstrated a favorable safety profile in clinical studies targeting other senescence-related conditions (Gonzales et al., 2022). An initial open-label clinical trial pilot illustrated that an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage AD. The primary objective is to evaluate the CNS penetration of dasatinib and quercetin by analyzing CSF collected at baseline and after 12 weeks of treatment; further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and AD-relevant cognitive and functional (Gonzales et al., 2022). Moreover, reduced levels of SIRT1 in the brains of patients with AD may be related to the decline in SOD-1 and neuropathological changes of this disorder. The number of both SIRT1-positive and SOD-1-positive neurons and the integrated optical density of immunohistochemical staining for these proteins in the temporal and frontal cortices and the hippocampus of patients with AD were significantly decreased compared with those in corresponding controls. In the cerebellum, very weak SIRT1 expression and strong SOD-1 expression were observed in granule cells, with no significant difference between the AD and control groups. Interestingly, the levels of SIRT1 and SOD-1 are dysregulated in all regions of the AD brains investigated, except the cerebellum (Cao et al., 2018).

Furthermore, PD is a progressive neurodegenerative disease characterized by the accumulation of mutant alpha-synuclein (α-Syn) and the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (Miller et al., 2023). It has been emphasized that senolytic and senomorphic agents improve PD neuropathology in D. melanogaster (Miller et al., 2023). Findings from a preclinical study demonstrated that α-Syn pathology could lead to astrocyte and/or microglia senescence in PD brains, which may contribute to neuropathology in this model (Verma et al., 2021). Therefore, targeting senescent cells using senolytics could constitute a viable therapeutic option for treating PD.

Significantly, SIRT1 influences brain-derived neurotrophic factor (BDNF) expression by deacetylating methyl-CpG binding protein 2 (MeCP2), a transcription factor implicated in Rett syndrome. This deacetylation promotes MeCP2 release from the BDNF promoter, thereby elevating BDNF transcription and release (Wang et al., 2023). Elevated SIRT1 expression, particularly in hippocampal neurons, may thus support synaptic plasticity by regulating dendritic spine remodeling and connectivity. Interestingly, BDNF attenuates the brain aging process and the development of neurodegenerative diseases. Findings from a preclinical study showed that decreased BDNF-TrkB signaling during aging favors microglial activation.

In contrast, upregulation of BDNF signaling inhibits microglial activation via the TrkB-Erk-CREB pathway in mice (Wu et al., 2020). As well, BDNF sequentially kinetic activated (SKA) counteracts mechanisms underlying CNS degeneration and aging by increasing endogenous protective mechanisms. Both in vitro and in vivo experiments demonstrated that BDNF SKA induces endogenous BDNF production via its receptor TrkB and influences ApoE4 expression. Moreover, BDNF SKA exerted effects on β-Amyloid and SIRT1 proteins, confirming the hypothesis of a fine endogenous regulatory role in maintaining the health of both neurons and astrocytes (Molinari et al., 2020). For this reason, a change in BDNF turnover is considered a positive factor in the fight against brain aging. Significantly, senolytic agents that eradicate senescent neurons can improve cognitive function. Senolytic treatment of AD mice selectively removed senescent cells from the plaque environment, reduced neuroinflammation, lowered Aβ load, and ameliorated cognitive deficits [49], suggesting a potential role for senolytic agents in aging and aging-related neurodegeneration. These findings indicated that impairment of neuroprotective SIRT1 signaling contributes to the brain aging process (Table 2).

Furthermore, SIRT1 is highly dysregulated in the aging brain and related processes. SIRT1 has an anti-aging effect by deacetylating different proteins involved in cellular pathways such as apoptosis and stress response (Chen et al., 2020). In mice, SIRT1 expression declines with age, whereas enhanced SIRT1 activity has been shown to prolong lifespan in both yeast and mice. Recently, considerable attention has been given to how external factors, such as polyphenol dietary compounds with epigenetic effects, can regulate molecular processes linked to aging. These natural agents influence cellular longevity by modifying histones post-translationally and by promoting autophagy, which reduces acetyl coenzyme A (AcCoA) availability. A pilot study showed that plasma SIRT1 levels were lower in healthy elderly volunteers than in healthy controls (Libri et al., 2012). SRT2104 has been developed as a selective small molecule activator of SIRT1, which regulates energy homeostasis and modulates various metabolic pathways, including glucose metabolism, oxidative stress, and lipid metabolism (Libri et al., 2012).

A pilot randomized, placebo-controlled, double blind phase I trial showed that SRT2104 was generally safe and well-tolerated. Pharmacokinetic exposure increased less than dose-proportionally with increased mitochondrial oxidative phosphorylation (Libri et al., 2012). In addition, plasma SIRT1 levels are reduced in elderly patients with ischemic stroke, a common CNS disorder in aging (Esmayel et al., 2021). Plasma SIRT1 levels are lower in patients with acute cerebrovascular stroke than in controls. Also, SIRT1 may be a possible biomarker for predicting the risk of acute cerebrovascular stroke. Notably, in healthy individuals, plasma SIRT1 concentrations correlate with age, body mass index, indicators of carbohydrate metabolism, and markers of antioxidant status. A comparison between individuals with accelerated aging and those aging normally revealed significant differences in SIRT1 plasma levels (Kolesnikova et al., 2023). Nonetheless, this study did not establish a link between SIRT1 gene polymorphisms and variations in plasma SIRT1 levels, aging pace, or metabolic traits. Substantial research has shown that oxidative stress and inflammation are major contributors to age-related degeneration in peripheral tissues. Yet, there is relatively little evidence clarifying their role in the normal aging process of the brain. Elevated oxidative damage, however, has been associated with critical cellular alterations, including diminished NAD availability (Guest et al., 2014). In addition, progressive aging is associated with increased oxidative damage, inflammation, and reduced NAD in the brain (Guest et al., 2014).

Furthermore, CSF SIRT1 levels are lower in elderly patients than in young subjects (Guest et al., 2014). Additionally, it has been shown that microglial SIRT1 deficiency is associated with memory impairment and accelerated aging in mice, due to upregulation of the inflammatory response (Guest et al., 2014). Chronic inflammation and aging microglia contribute to neurodegenerative cognitive deficits. Consistently, a decline in SIRT1 accompanies microglial aging, and loss of SIRT1 in microglia contributes to aging-related processes and tau-associated memory impairments through increased IL-1β expression in mice (Cho et al., 2015). This selective rise in IL-1β transcription may result from hypomethylation at specific regions of its proximal promoter caused by SIRT1 deficiency. In humans, IL-1β hypomethylation is closely associated with advancing chronological age and increased IL-1β gene expression (Guest et al., 2014). Thus, aging-induced SIRT1 deficiency in the brain contributes to the development and progression of cognitive decline and memory deficits [Table 3].

Therefore, the aging process distorts the brain SIRT1 signaling pathway, leading to cognitive impairment and neurodegeneration. Thus, SIRT1 activators may restore and reverse brain aging.

Although increasing evidence supports SIRT1 as a major regulator of aging-associated pathways, several limitations should be considered when interpreting its relevance as a therapeutic target in brain aging (Guarente, 2011; Imai & Guarente, 2014). A large proportion of available data originates from preclinical studies using heterogeneous models, variable intervention timing, and different outcome measures, which may not fully capture the slow and multifactorial nature of physiological brain aging in humans (Kennedy et al., 2014). In addition, SIRT1 functions in a highly context-dependent manner, and its effects may differ across brain regions and between neurons and glial populations, complicating the identification of uniform mechanisms and therapeutic endpoints (Herskovits & Guarente, 2014). From a translational perspective, pharmacological modulation of SIRT1 faces practical challenges, including limited bioavailability, uncertain brain penetration of some compounds, potential off-target effects, and difficulties in defining optimal dosing and treatment duration (Baur & Sinclair, 2006). Moreover, since aging is not a pathological condition per se, the aim of SIRT1 modulation should be framed as supporting neuronal resilience, preserving homeostasis, and delaying functional decline, rather than treating aging itself as a disease. A key knowledge gap remains the identification of reliable biomarkers of CNS target engagement to monitor SIRT1 modulation and predict neuroprotective benefit (Rajman et al., 2018).

Despite promising preclinical evidence, the translational potential of SIRT1 activators in brain aging remains uncertain. Most available data derive from in vitro and animal studies, whereas clinical evidence in humans remains limited and heterogeneous. In addition, pharmacokinetic challenges, including low oral bioavailability, rapid metabolism, and variable blood–brain barrier penetration, may restrict the therapeutic effectiveness of several candidate compounds such as resveratrol. Furthermore, the mechanism by which some polyphenols modulate SIRT1 activity remains debated, as some studies suggest that their effects may occur indirectly through upstream metabolic regulators such as AMPK or by modulating cellular NAD⁺ metabolism rather than through direct activation of SIRT1.

Finally, while multiple SIRT1-modulating strategies have shown promising outcomes in preclinical settings, clinical evidence supporting clear benefits for brain aging phenotypes remains limited and heterogeneous. Future studies should prioritize aged and clinically relevant models, incorporate standardized cognitive and neurobiological endpoints, and clarify therapeutic windows and cell-type specificity. Well-designed clinical trials integrating cognitive measures with molecular and imaging biomarkers will be essential to determine whether SIRT1-targeting interventions can be translated into meaningful benefits for age-associated cognitive decline and neurodegenerative vulnerability (Rajman et al., 2018).

Aging is a multifactorial process that affects various tissues, including the brain. SIRT1 is necessary for brain development and control of brain senescence by promoting axonal growth, dendritic branching, and neurite outgrowth. In addition, SIRT1 enhances memory function by activating synaptic plasticity and preventing age-related neurodegeneration and cognitive decline. SIRT1 has an anti-aging effect by deacetylating different proteins involved in cellular pathways, such as apoptosis and stress response. Therefore, SIRT1 has neuroprotective effects against the development and progression of brain aging and related neurodegenerative diseases. Notably, SIRT1 is highly dysregulated in the aging brain and other aging processes. Therefore, SIRT1 activators may be a promising therapeutic strategy against brain aging. SIRT1 activators, such as Resveratrol, metformin, and statins, have neuroprotective effects against brain aging by regulating inflammatory and oxidative stress pathways through modulation of downstream signaling pathways. Additional preclinical and clinical studies are warranted in this regard. The more thorough clinical study is therefore suggested to elucidate these findings.

Ayman Ali Mohammed Alameen: Revision. Hayder M. Al-kuraishy and Ali I. Al-Gareeb: Collected the related research literature and papers and drafted the manuscript. Athanasios Alexiou, Marios Papadakis; Revision, and funding. Safaa A. Faheem: Visualization, Software, and writing –review and editing, Gaber El-Saber Batiha: Conceptualization. All authors have approved and read the final manuscript.

Open access funding provided by HEAL-Link Greece. No funding.

This manuscript does not report data generation or analysis.

Marios Papadakis, Email: mapapadakis@uth.gr, Email: drmariospapadakis@gmail.com.

Safaa A. Faheem, Email: safaa-faheem@eru.edu.eg

Gaber El-Saber Batiha, Email: Gaberelsaberbatiha@gmail.com.