Abstract
Prolonged lifespan and improved health in late adulthood can be achieved by partial inhibition of mitochondrial proteins in yeast, worms, fruit flies, and mice. Upregulation of the mitochondrial unfolded protein response (mtUPR) has been proposed as a common pathway in lifespan extension induced by mitochondrial defects. However, it is not known whether mtUPR is elevated in long‐lived mouse models. Here, we report that Snell dwarf mice, which show 30%–40% lifespan extension and prolonged healthspan, exhibit augmented mitochondrial stress responses. Cultured cells from Snell mice show elevated levels of the mitochondrial chaperone HSP60 and mitochondrial protease LONP1, two components of the mtUPR. In response to mitochondrial stress, the increase in Tfam (mitochondrial transcription factor A), a regulator of mitochondrial transcription, is higher in Snell cells, while Pgc‐1α, the main regulator of mitochondrial biogenesis, is upregulated only in Snell cells. Consistent with these differences, Snell cells maintain oxidative respiration rate, ATP content, and expression of mitochondrial‐DNA‐encoded genes after exposure to doxycycline stress. In vivo, compared to normal mice, Snell mice show stronger hepatic mtUPR induction and maintain mitochondrial protein stoichiometry after mitochondrial stress exposure. Overall, our work demonstrates that a long‐lived mouse model exhibits improved mitochondrial stress response, and provides a rationale for future mouse lifespan studies involving compounds that induce mtUPR. Further research on mitochondrial homeostasis in long‐lived mice may facilitate development of interventions that blunt mitochondrial deterioration in neurodegenerative diseases such as Alzheimer's and Parkinson's and postpone diseases of aging in humans.
Highlights
Primary fibroblasts isolated from Snell mice are more resistant to cell death induced by UV radiation, hydrogen peroxide, cadmium, and paraquat (Murakami et al, 2003)
Increased mitochondrial stress resistance observed at the cellular level in Snell fibroblasts was consistent with higher mitochondrial unfolded protein response (mtUPR) (HSP60 and LONP1) levels detected (Fig. 2.1, 2.2)
Confirming previous findings (Page et al, 2009), analysis of mitochondrial protein levels (Fig. 2.3) and mitochondrial DNA" (mtDNA) content indicated that mitochondrial abundance was comparable in normal and Snell cells (Fig 2.4), suggesting that elevated expression levels of HSP60 and LONP1 in Snell fibroblasts cannot be explained by alterations in mitochondrial content, but indicate upregulation of mtUPR in fibroblasts isolated from long-lived Snell mice
Summary
Aging can be defined as the process of progressive decline in the function and form of organisms starting at adulthood. It is generally thought to be driven by concurrent deterioration of multiple cellular structures and molecular pathways – a comprehensive understanding of this process is still lacking. Aging research investigates the molecular mechanisms underlying agingassociated deterioration with the aim of utilizing the ensuing insights to develop interventions to slow down the aging process and prolong lifespan and healthspan in mammals
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