Premature aging in mice activates a systemic metabolic response involving autophagy induction

Abstract

Autophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis. It is well-established that the basal autophagic activity of living cells decreases with age, thus contributing to the accumulation of damaged macromolecules during aging. Conversely, the activity of this catabolic pathway is required for lifespan extension in animal models such as Caenorhabditis elegans and Drosophila melanogaster. In this work, we describe the unexpected finding that Zmpste24-null mice, which show accelerated aging and are a reliable model of human Hutchinson-Gilford progeria, exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging. We also show that this autophagic increase is associated with a series of changes in lipid and glucose metabolic pathways, which resemble those occurring in diverse situations reported to prolong lifespan. These Zmpste24(-/-) mice metabolic alterations are also linked to substantial changes in circulating blood parameters, such as leptin, glucose, insulin or adiponectin which in turn lead to peripheral LKB1-AMPK activation and mTOR inhibition. On the basis of these results, we propose that nuclear abnormalities causing premature aging in Zmpste24(-/-) mice trigger a metabolic response involving the activation of autophagy. However, the chronic activation of this catabolic pathway may turn an originally intended pro-survival strategy into a pro-aging mechanism and could contribute to the systemic degeneration and weakening observed in these progeroid mice.

Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function

“…In addition to the reported changes in glucose and lipid metabolism genes (17,18) and the marked up-regulation of components of the p53-signaling pathway (9), we observed that many genes involved in somatotroph axis signaling were transcriptionally altered in the liver of Zmpste24 −/− mice (Table 1). To further evaluate these results, we performed a quantitative PCR (qPCR) analysis of selected GH/IGF-1 axis genes in liver samples from Zmpste24 −/− mice.…”

“…Interestingly, some pathological features of LS are also found among the complex phenotypic manifestations of these progeroid mice. Both Zmpste24 −/− mice and LS patients have reduced muscle development, strength, and endurance, as well as decreased bone mineral density, and both exhibit alopecia, skin atrophy, and hypoglycemia (8,16,17).…”

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

“…Increased autophagy has been observed in premature aging mice. 31,37 To investigate whether rescued mnd2 mice exhibit increased autophagosome activity, we examined the ratio of autophagosome marker LC3-II/LC3-I in cardiac and skeletal muscles of rescued mnd2 and control animals. Indeed, the ratio of LC3-II/LC3-I was significantly higher in cardiac and skeletal muscles of aged rescued mnd2 mice than in corresponding tissues of control littermates (Figure 5a).…”

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

“…Hepatic steatosis is a common phenotype for aged mice (Jin et al., 2010; Ogrodnik et al., 2017), Zmpste24 mutants (Marino et al., 2008; Pendas et al., 2002), and liver‐specific Lmna knockouts (Kwan et al., 2017). In addition, mutations in LMNA and ZMPSTE24 in patients lead to metabolic dysfunction, including type 2 diabetes and hepatic steatosis (Galant et al., 2016; Shackleton et al., 2000).…”