Does autophagy take a front seat in lifespan extension?
Bottom Line: Ageing and ageing-mediated defective autophagy involve accumulation of lipofuscin.Nutritional deprivation or calorie restriction as well as several nutriceuticals including resveratrol, spermidine, curcumin and piperine can enhance autophagy and increase lifespan.Such striking similarities indicate that lifespan is strongly dependent on autophagy.
Affiliation: Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.Show MeSH
Mentions: The large plethora of signalling pathways intersecting at the three major degradative pathways (lysosomal, autophagosomal and proteasomal) is ultimately what decides the balance between ageing and longevity (Fig. 1). Although the death due to ageing for human beings is difficult to correlate because many old people die from other factors such as cardiovascular disease, cancer or diabetes independent of ageing, lifespan and ageing are easy to correlate for lower eukaryotic species. For example, the lifespan of Caenorhabditis elegans can be extended simply by blocking pro-ageing genes . Compared to wild-type C. elegans, mutant species lacking insulin/IGF-1 receptor (Daf-2) live twice their age . Insulin receptor in turn activates class I PI3K-Akt signalling pathway, leading to the inhibition of FoxO-–putative player in the human ageing process (Figs. 1 and 2) [20, 21]). This would tend to suggest that inactivation of PI3K/Akt and activation of FoxOs would extend the lifespan of C. elegans[22, 23]. A mitogen-activated kinase member JNK also modulates FoxO and plays a role in the ageing process . The cytokines also appear to be involved as TGF-β signalling seems to be instrumental for autophagy . In addition, mTOR signalling and AMPK (AMP-activated protein kinase) signalling also appear to be involved in the ageing process [26, 27].
Affiliation: Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.