Progress in the genetics of aging field has demonstrated that, while chronological aging is unavoidable, biological aging is malleable, and targeting cellular processes to promote homeostasis is an alternative strategy to disease based approaches to alleviate the health burdens of old age. Both environmental conditions and conserved genetic pathways strongly influence the rate of physiological aging and organisms alter the rate at which they age and succumb to disease in response to external cues. The most potent example of this is dietary restriction (DR), reduced food intake without malnutrition, which slows aging in every organism tested thus far and protects against multiple chronic diseases, including cancer, cardiovascular disease and neurodegeneration. Our long-term objective is to elucidate how DR promotes healthy aging to allow the development of novel therapeutics to treat age-related disease. Multiple molecular mechanisms have been implicated as critical mediators of DR, including the Target of rapamycin complex 1 (TORC1) and AMP-activated protein kinase (AMPK), conserved nutrient sensors that antagonistically modulate metabolism and ageing. Surprisingly however, how and where AMPK and TORC1 interact to modulate systemic aging is unclear. We find that neuronal AMPK is essential for lifespan extension from TORC1 inhibition in C. elegans. Further, lifespan extension by null mutations in raga-1 (an upstream TORC1 activator) or rsks-1 (homologue of mammalian S6K) is fully suppressed by neuronal specific recues. Neuronal RAGA-1 abrogates raga-1 mutant longevity via neuropeptide signalling. Previously we have identified key roles for regulation of mitochondrial dynamics and RNA splicing in AMPK and TORC1 longevity respectively. We now show that these downstream effectors receive neuronal signals mediated by TORC1 to modulate aging. Our results highlight a new role for neuronal TORC1 in cell non-autonomous regulation of metabolism, RNA homeostasis and ageing, and suggest TORC1 in the central nervous system might be targeted to promote healthy ageing. Our central hypothesis is therefore that the beneficial effects of DR may be recapitulated via identification of cell nonautonomous signals regulated by neuronal TORC1. The objective of this application is to define the specific neuronal signals mediated by TORC1 that pertain to healthy aging, and how these signals are received in peripheral tissues to modulate mitochondrial networks and RNA splicing to promote longevity.
This proposed research is relevant to the mission of the NIH because uncovering the underlying mechanisms by which neuronal signals downstream of nutrient sensing regulate healthy aging cell nonautonomously will provide novel therapeutics to both prevent and cure diseases of old age, which represent an ever growing burden to public health.
