“ The mechanistic target of rapamycin (mTOR) pathway is an important integrator of processes involved in aging and longevity, coordinating nutrient sensing, metabolic adaptation, and cellular stress responses .”
BUFFALO, NY — October 20, 2026 — A new review was published in Volume 18 of Aging on September 19, 2026, titled “ mTOR signaling in aging: from causality to geroprotective interventions and hallmark-level outcomes .”
The review examines how the mechanistic target of rapamycin (mTOR) signaling pathway influences aging, longevity and age-related diseases. Drawing on evidence from molecular research, animal experiments and human studies, it highlights mTOR as a central regulator of cellular metabolism, stress adaptation and tissue maintenance. The evidence reviewed suggests that carefully controlled modulation of mTOR signaling could support future strategies for healthy aging, although its long-term benefits in humans remain unproven.
The review was authored by Natalia Bobok, Chief Scientific Officer at INSTYTUTUM AG , Zug, Switzerland.
Aging involves interconnected biological changes, including mitochondrial dysfunction, cellular senescence, impaired protein maintenance and declining regenerative capacity. The mTOR pathway helps coordinate many of these processes by responding to nutrient availability, growth factors and cellular stress. However, while excessive mTOR activity has been associated with age-related dysfunction, completely suppressing the pathway may interfere with essential functions such as tissue repair, metabolism and immune regulation.
The review synthesizes evidence from 265 publications and organizes the findings into three major areas: the biological role of mTOR in aging, interventions that influence its activity, and its interactions with the hallmarks of aging and age-related diseases. This framework emphasizes that mTOR operates as a dynamic signaling network rather than a single molecular switch.
A central distinction concerns the two major mTOR complexes, mTORC1 and mTORC2, which regulate overlapping but different cellular functions. mTORC1 primarily responds to nutrients and growth signals, promoting protein synthesis, cellular growth and metabolism while restraining autophagy, the process through which cells recycle damaged components. Persistent mTORC1 activation can contribute to reduced cellular maintenance and impaired adaptation to stress.
In contrast, mTORC2 regulates pathways involved in insulin signaling, glucose metabolism, cell survival and stress responses through proteins such as AKT, PKC and SGK. Its effects on aging are more complex and tissue-dependent. Experimental studies indicate that preserving mTORC2 activity may support metabolic stability and regenerative functions in certain settings, while excessive activation can be harmful in others. These differences make selective regulation of the two complexes particularly important.
The review also evaluates evidence connecting mTOR signaling to lifespan regulation. Genetic and pharmacological studies have demonstrated that reducing TOR/mTOR signaling can extend lifespan in several experimental organisms, including yeast, worms, flies and mice. Comparative research has also identified lower mTORC1-related activity and distinct pathway characteristics in some exceptionally long-lived mammalian species.
However, the strength of evidence differs between experimental models and humans. While animal studies support a causal relationship between mTOR signaling and lifespan regulation, human findings remain largely associative. Genetic studies of exceptionally long-lived individuals have identified variants in mTOR-related pathways, but these observations do not establish that modifying the pathway will extend human lifespan.
An important therapeutic mechanism involves autophagy. When mTORC1 activity is reduced during nutrient or energetic stress, cells can increase the breakdown and recycling of damaged proteins and organelles. This process contributes to cellular quality control and may help counteract age-associated dysfunction. Nevertheless, the review emphasizes that autophagy is regulated by multiple pathways, including AMPK, SIRT1 and FOXO, and that its benefits cannot be attributed exclusively to mTOR inhibition.
Dietary interventions are another major focus. Caloric restriction, intermittent fasting and selected dietary patterns can influence mTORC1 activity while activating additional metabolic and stress-response pathways. These adaptations may improve metabolic flexibility, autophagic activity and cellular resilience in experimental settings. However, their effects depend on energy intake, nutrient composition, age and physiological condition, making it inappropriate to assume that all forms of dietary restriction produce equivalent benefits.
Physical activity also influences mTOR signaling through repeated cycles of energy use and recovery. During exercise, AMPK activation can help promote cellular maintenance and metabolic adaptation, while mTORC1 activity may increase during recovery to support protein synthesis and muscle repair. This dynamic balance illustrates why healthy aging may depend more on flexible pathway regulation than sustained inhibition.
The review further examines senotherapeutics, treatments designed to target cellular senescence. Senescent cells can accumulate with age and release inflammatory molecules through the senescence-associated secretory phenotype (SASP), contributing to chronic inflammation and tissue dysfunction. mTORC1 helps regulate certain SASP-related processes, making it a potential target for interventions that reduce harmful inflammatory signaling.
Rapamycin and related drugs are among the most extensively studied mTOR inhibitors. Experimental studies have demonstrated lifespan extension in mice, including when treatment begins later in life. Rapamycin can also suppress selected SASP-related processes without necessarily eliminating senescent cells, supporting its potential role as a senomorphic intervention.
Early clinical studies have reported that low-dose mTOR inhibition can improve selected immune responses in older adults, including responses to influenza vaccination. More recent trials have also explored the tolerability of intermittent low-dose rapamycin. However, these findings do not establish that rapamycin extends human lifespan or broadly improves healthspan.
Safety remains a major concern. Prolonged or excessive mTOR inhibition can impair wound healing, immune function, glucose regulation and tissue maintenance. Chronic rapamycin exposure may also interfere with mTORC2 signaling in certain tissues, potentially contributing to metabolic complications. Although intermittent dosing may offer theoretical advantages, sufficient human evidence is not yet available to establish an optimal geroprotective regimen.
“ Gerotherapeutic strategies must consequently favor selective and temporally controlled modulation over uniform pathway inhibition. ”
Beyond individual interventions, the review examines how mTOR signaling intersects with multiple hallmarks of aging. These include mitochondrial dysfunction, stem cell exhaustion, genomic instability, epigenetic alterations, loss of proteostasis and cellular senescence. By coordinating metabolism, protein synthesis and stress responses, mTOR influences several biological processes that contribute to age-related functional decline.
The review also connects these mechanisms to cardiovascular disease, neurodegeneration, metabolic disorders and sarcopenia. For example, excessive mTORC1 activity can contribute to impaired mitochondrial maintenance and inflammatory signaling, while excessive inhibition may compromise muscle regeneration or cardiac function. These opposing effects reinforce the importance of tissue-specific treatment strategies.
The review has important limitations. As an integrative narrative review, it combines findings from diverse experimental and clinical studies rather than presenting new experimental results or a quantitative meta-analysis. Much of the mechanistic evidence comes from animal and cellular models, while human trials remain relatively small and focused on selected physiological outcomes. Differences in study design, treatment schedules and biological models also limit direct comparisons.
Future research will need to establish reliable biomarkers of mTORC1 and mTORC2 activity, identify appropriate treatment schedules and determine which individuals might benefit from selective pathway modulation. Large randomized trials with clinically meaningful outcomes will be essential before mTOR-targeted interventions can be recommended specifically to promote human longevity.
Overall, the review identifies mTOR as an important regulator connecting multiple hallmarks of aging with potential geroprotective interventions. Rather than supporting indiscriminate pathway suppression, the findings emphasize restoring the balance between cellular growth, maintenance and stress adaptation. This approach provides a scientific foundation for investigating more precise and individualized strategies to support healthy aging.
Paper DOI : https://doi.org/10.18632/aging.206423
Corresponding author: Natalia Bobok - Natalia.bobok@instytutum.com
Abstract video: https://www.youtube.com/watch?v=d5Ogq6Myfis
Keywords: aging, mTOR signaling, mTORC1, mTORC2, geroprotective interventions, hallmarks of aging
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Aging-US
Literature review
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mTOR signaling in aging: from causality to geroprotective interventions and hallmark-level outcomes
19-Sep-2026
The authors declare that they have no conflicts of interest.