Snell dwarf mice in which growth hormone has been disabled live significantly longer than their peers. Suppression of growth hormone activity is one of the better studied interventions known to slow aging in mice, and, like calorie restriction, has led to a strong focus on stress response mechanisms in the aging research community. A majority of the means of slowing aging in short-lived laboratory species are characterized by increased cellular maintenance activities that are triggered into greater efforts by cellular stresses: heat, cold, lack of nutrients, an excess of toxic or reactive molecules, and so forth.
Declining mitochondrial function is a characteristic of aging, as quality control mechanisms falter in their operation with advancing age. Researchers here show that one of the mechanisms associated with maintaining correct mitochondrial function, the unfolded protein response, is more active in Snell dwarf mice. This is consistent with what is already known of the slowed aging in this and similar lineages, and of the importance of cellular maintenance and mitochondria in aging.
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.