Fight Aging!

Most of the varied approaches shown to modestly slow the progression of aging appear to operate through a small number of common mechanisms, largely involving the cellular response to stress. Some of those mechanisms will turn out to be more influential than others, though little progress has been made towards assigning relative importance to the various layers of the exceedingly complex reactions to heat, cold, restriction of nutrients, and other forms of mild stress that can produce beneficial outcomes.

The most compelling evidence to date suggests that improved autophagy is one of the more relevant portions of the cellular response to stress, a greater recycling of worn and damaged cell components leading to improved function over time. Here, researchers discuss TFEB, a regulator of autophagy, in the context of interventions shown to slow aging. In this context, it is worth noting that stress response enhancement of longevity appears to produce much larger effects in short-lived species than in long-lived species. In the two cases where one can compare fairly directly compare humans with mice, the practice of calorie restriction and loss of function mutations in growth hormone signaling, there is no evidence for a sizable increase in life span in our species.

TFEB is a central regulator of the aging process and age-related diseases

Extending lifespan or delaying aging has been shown to protect against degenerative diseases, and interventions that slow down the normal aging process can ameliorate multiple age-related pathologies and increase lifespan. For this reason, age-related diseases may be viewed as organ-specific conditions of accelerated aging. Therefore, slowing down the aging process is vital to prevent age-associated diseases.

Transcription factor EB (TFEB) is a key transcriptional regulator of autophagy and lysosomal biogenesis. Laboratory experiments in model organisms demonstrated that TFEB overexpression promoted longevity and reduced the burden of diseases. In rodents, healthy lifestyle interventions, such as caloric restriction and physical activity, were found to activate TFEB and upregulate autophagy, leading to a lower disease burden and extended lifespan. Pharmacological activators of TFEB, such as metformin and trehalose, also promoted autophagy and therapeutic benefits similar to caloric restriction and physical exercise. In humans, the dysregulation of TFEB is implicated in aging and diseases. Clinical trials are underway to test the safety and efficacy of caloric restriction mimetics known for their potent activation of TFEB and autophagy, such as metformin, trehalose, resveratrol, and spermidine.

Understanding the functional role of TFEB in the aging process and disease could help in the development of new therapeutic interventions for treating age-related diseases, which can extend lifespan. In this review, we provide up-to-date information on the contributions of TFEB activation in the modulation of the various hallmarks of aging and discuss the specific impact these may have on different tissues in the context of aging and age-related diseases. Furthermore, we argue that TFEB activation is a vital effector mechanism by which healthy lifestyle behaviors including caloric restriction, intermittent fasting, and exercise prevent diseases and extend lifespan.