Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling

Abstract

Summary Mitochondrial network remodeling between fused and fragmented states facilitates mitophagy, interaction with other organelles and metabolic flexibility. Aging is associated with a loss of mitochondrial network homeostasis, but cellular processes causally linking these changes to organismal senescence remain unclear. Here, we show that AMP-activated protein kinase (AMPK) and dietary restriction (DR) promote longevity in C. elegans via maintaining mitochondrial network homeostasis and functional coordination with peroxisomes to increase fatty acid oxidation (FAO). Inhibiting fusion or fission specifically blocks AMPK- and DR-mediated longevity. Strikingly however, preserving mitochondrial network homeostasis during aging by co-inhibition of fusion and fission is sufficient itself to increase lifespan, while dynamic network remodeling is required for intermittent fasting-mediated longevity. Finally, we show that increasing lifespan via maintaining mitochondrial network homeostasis requires FAO and peroxisomal function. Together these data demonstrate that mechanisms that promote mitochondrial homeostasis and plasticity can be targeted to promote healthy aging.

Multi‐omics identify xanthine as a pro‐survival metabolite for nematodes with mitochondrial dysfunction

“…We measured ATP and oxygen consumption rate (OCR) in gas-1 and age-1; gas-1 mutants. Since altered mitochondrial connectivity can influence C. elegans metabolism in several lifespan-extending paradigms (Yang et al, 2011;Chaudhari & Kipreos, 2017;Han et al, 2017;Weir et al, 2017), we reasoned that a more fused mitochondrial network may play a causative role for age-1; gas-1 longevity. Intriguingly, we found that IIS inhibition improved the maintenance of a more fused mitochondrial network as revealed by super-resolution STED microscopy and fluorescence recovery after photobleaching (FRAP) experiments in animals expressing a mitochondrial GFP in the muscle (Fig 1I and J,and Appendix Fig S1G).…”

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

“…Interestingly, median lifespan extension (as well as slowing of the decline in locomotion of aging worms, a surrogate marker of health-span) was greater with intermittent fasting than persistent calorie restriction in worms, and mechanistically transduced via suppression of insulin signaling and upregulation of DAF16 (the worm orthologue of FOXO) (88). Subsequent studies demonstrate that remodeling of mitochondrial networks with fasting and re-feeding plays a critical role in the metabolic effects of intermittent fasting, as worms deficient in mitochondrial fusion ( fzo-1 ) and fission ( drp-1 ) genes did not derive the lifespan extension benefits of intermittent fasting, despite being long-lived under nutrient replete conditions (230). Our studies with intermittent fasting in a mouse model of obesity-induced diabetes (a model of type 2 diabetes with insulin resistance) demonstrated preservation of β-cell mass and insulin-secretory capacity despite continued high fat diet feeding, due to attenuated β-cell death and a dramatic upregulation of endocrine progenitor markers in the islet and per-islet tissue suggesting β-cell regeneration (119).…”

Causal roles of mitochondrial dynamics in longevity and healthy aging

“…Interestingly, eat‐3 RNAi by itself did not alter the lifespan of wild‐type animals. Additionally, RNAi of drp‐1 or overexpression of the mitofusin ortholog FZO‐1, both of which increase mitochondrial fusion, does not increase lifespan in C. elegans .…”