Rapamycin, anti-aging, and avoiding the fate of Tithonus

Abstract

The discovery that rapamycin increased the lifespan of mice was recognized by Science as one of the top 10 scientific breakthroughs of 2009. In addition to increasing lifespan, Neff and colleagues show that while rapamycin improves several functions/pathologies that change with age, it has little effect on the majority of the physiological and structural parameters they evaluated. What do these data tell us about the ability of rapamycin to delay aging and improve quality of life, i.e., prevent the fate of Tithonus?The Tithonus effect The consequences of longevity without health and vigor are dramatically portrayed in the Greek myth about Tithonus, a prince of Troy. After the goddess Eos kidnapped him, she asked Zeus to make Tithonus immortal. Unfortunately, Eos forgot to ask for eternal youth. (1) reported that rapamycin (also known as sirolimus) increased both mean and maximum lifespan of mice, demonstrating that all competing causes of mortality (i.e., age-related diseases) are delayed and suggesting that rapamycin slows aging. Because rapamycin is approved by the FDA for transplant and cancer patients, this discovery has enormous translational potential; however, before taking a potential anti-aging therapy to humans, it is necessary to demonstrate that the agent does not produce a "Tithonus phenotype," where the increase in lifespan is accompanied by more disability and disease and a greater loss of physiological functions, i.e., a reduced quality of life. A comprehensive assessment of aging in miceIn this issue of the JCI, Neff et al. (2) describe the results from their large-scale study of the effect of rapamycin on more than 150 aging phenotypes across 25 different tissues in male C57BL/6 mice. They identified several aging phenotypes that were improved by rapamycin, in particular behavior/cognition, several immune parameters, and a number of pathological lesions. The effect of rapamycin on cognition is particularly important in an aging context because this physiological domain is critical for the quality of life in humans. Neff et al. (2) showed that learning and memory were improved. Halloran et al. (3) and Majumder et al. (4) also found that rapamycin improved the performance of old mice. Furthermore, rapamycin was previously observed to restore memory in transgenic mouse models of Alzheimer's disease (5-7). Thus, the current data indicate that rapamycin has a robust effect on cognitive performance in mice.Neff et al. (2) found that the vast majority of parameters they measured were not significantly altered by rapamycin, including vision, hearing, and cardiac and skeletal muscle function, all of which are important to quality of life. Rapamycin has been found to improve cardiac function in old mice (P. Rabinovitch, personal communication) and in Lmna -/-mice (8). While Neff et al. (2) saw no effect of rapamycin on muscle function using measurements of grip strength and rotarod performance (a measure of muscle function as well as balance and motor coordination), Zhang et al. (9) found that rotarod ...

eRapa Restores a Normal Life Span in a FAP Mouse Model

“…However, nephrotoxicity was not found in other studies on C57BL/6 mice (16) or HET-3 mice (14). Thus, the only common toxicity associated with chronic rapamycin treatment is testicular degeneration (39). …”

Sirtuins: guardians of mammalian healthspan

“…To prove that SIRT1 and SIRT6 slow aging in mice, many more studies are required to comprehensively elucidate the impact of increased levels of these proteins on diverse age-sensitive traits in different tissues, as has been done in the context of dietary restriction (BOX 3) and reduced growth hormone signaling [6]. Recent controversies in the literature regarding whether the mTOR inhibitor rapamycin truly delays aging emphasize the difficulty of establishing a primary effect of a singular intervention on aging [58–60]. …”

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

“…(164) The mechanisms of the effect of rapamycin are pleiotropic, including inhibition of protein synthesis, alteration of transcriptomes, modulation of inflammation, and improvement of cerebral blood flow, in addition to regulation of autophagy, mitophagy and thereby mitochondrial function. (157,161,(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175)(176)(177) Taken together, these examples provide strong support for the concept that autophagy plays a critical role in maintaining a normal lifespan and healthy neuronal aging, and that its decline is inexorably tied to age related pathologies ( Figure 5). (178) Degradation of dysfunctional mitochondria is carried out by the autophagy-lysosomal pathway.…”