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 Zmpste 24-/-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.

dx.doi.org/10.1093/hmg/ddn120, hdl.handle.net/1765/29930
Human Molecular Genetics
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Erasmus MC: University Medical Center Rotterdam

Mariño, G, Ugalde, A.P, Salvador-Montoliu, N, Varela, I, Quirós, P.M, Cadiñanos, J, … López-Otín, C. (2008). Premature aging in mice activates a systemic metabolic response involving autophagy induction. Human Molecular Genetics, 17(14), 2196–2211. doi:10.1093/hmg/ddn120