Aging and TOR: interwoven in the fabric of life

Abstract

Longstanding results with calorie and growth factor restriction plus recent results with the first interventional drug suggest that retarding the pace of aging to improve the quality of life of older people is at hand. The biological system targeted by these approaches is the target of rapamycin (TOR), which is central for cellular responses to a variety of stimuli including stressors, growth factors, and nutrients and energy states. That the life-extending response to reducing its activity is highly conserved from yeast to mammals is consistent with the evolution of aging as a strategy to preserve reproductive potential of young cells and animals.

Fig. 1

Mammalian target of rapamycin complex 1 signaling pertinent to aging. a In a replete or wild-type setting, mTORC1 receives inputs from growth factor receptors such as IGF-I via Akt and the tuberous sclerosis complex (TSC2). Energy status is monitored by AMPK, which also signals through TSC2. Recently it has been found that amino acids signal to mTORC1 via Rag GTPases (RagA-RagD) in conjunction with a regulator (Ragulator) complex on endosomal membranes (reviewed in reference [122]. Two major outputs of mTORC1 signaling are S6 kinase 1 (S6K1) and 4E-BP1 translation (cap dependent) repressor. Various types of cell stresses limit mTORC1 activity through p53 or Redd1/2 [123]. In this setting, mTORC1 promotes anabolic activities and is nonpermissive for autophagy. b mTORC1-directed interventions that reduce its activities and increase lifespan include CR (hypothetical at this point), genetic models with restriction of growth factor signaling [57, 58], and an mTOR inhibitor, rapamycin [63]. Biguanides, such as metformin, have been recently shown to inhibit mTORC1 indirectly via the nutrient (amino acid)-responsive Rag GTPases [95], and may promote longevity. This is an oversimplification of a much more complex system with increasingly varied cell autonomous and systemic functions [19]

Fig. 2

Snell dwarf mouse liver polysome profiles. a Plots show the reduced polysome profile of dwarf mice (souris naines) compared to normal size siblings (souris normales). b GH treatment of dwarf mice (souris naines traitées) restores the polysome profile. These are Figs. 2 and 1, respectively, from reference [77]