Metabolic interventions delay cellular senescence

Timothy Nacarelli

doi:10.17918/00008801

Cellular homeostasis is progressively diminished in multiple tissues during aging. Proliferation-arrested senescent cells accumulate within tissues and contribute towards reduced maintenance and repair and increased inflammation, a universal hallmark of age-related pathologies. Indeed, senescent cells are found at sites of age-related pathologies and thought to be a major contributor to aging and susceptibility to disease. In addition to the inability to divide and pro-inflammatory function, senescent cells exhibit distinct mitochondrial and metabolic changes. Studies have raised the possibility that senescent cells are metabolically reprogrammed and require these changes for the induction and maintenance of the senescent state. Highlighting a reciprocal relationship between mitochondrial dysfunction and cellular senescence, we show that mitochondrial stress can induce cellular senescence by signaling through the mTORC1 pathway. Rapamycin treatment and methionine restriction are two of the most effective and consistent regimens that extend the lifespan of rodents and have been shown to delay cellular senescence, extending the replicative lifespan of cells in vitro. Each intervention provides resistance to mitochondrial stress and alterations that induce and accompany cellular senescence. We show that rapamycin treatment and methionine restriction have complementary effects when simultaneously administered and extend replicative lifespan further than either regimen alone. Combinatorial rapamycin treatment and methionine restriction altered status of nutrient sensing pathways including inhibition of mTORC1 signaling and activation of GCN2 signaling, resulting in enhanced autophagy and mitochondrial biogenesis with enrichment in particular mitochondrial regulatory proteins including UCP2. These alterations were associated with enhanced mitochondrial function and metabolic flexibility that may aid in the bioenergetic demand for cellular maintenance and proliferation, resulting in improved cellular longevity. Through improving mitochondrial homeostasis, combinatorial rapamycin treatment and methionine restriction metabolically intervene with cellular aging and senescence, and have potential in slowing the aging process in vivo.

Metabolic interventions delay cellular senescence

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Metabolic interventions delay cellular senescence

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