Inhibition of Autophagy in Mice Produces Signs of Accelerated Aging

One must always be careful in the interpretation of studies of aging in which essential biological processes are disrupted. There are any number of ways to disrupt essential biological functions to produce all sorts of consequent damage. But damage that isn't relevant to the normal processes of aging can nonetheless produce results that look very much like age-related conditions. Thus the details matter greatly. Here researchers suppress autophagy in mice in order to gain greater insight into its role in aging, and suggest that there might be reasons for caution in the development of therapies to boost autophagy in old people - though again, the details matter greatly in any interpretation of this work.

Autophagy is the name given to a collection of cellular maintenance processes that work to recycle damaged protein machinery and structures. Autophagy declines with age, and this loss may be of greatest relevance when it comes to removal of worn and dysfunctional mitochondria. Mitochondrial function falters with age, which causes issues throughout the body, particularly in energy-hungry tissues such as the brain and muscle. This appears to be connected to a reduced effectiveness of mitochondrial autophagy, though the causes of this issue are still being investigated.

It is well known that many of the interventions known to slow aging in mice involve upregulation of autophagy, and some, like calorie restriction, will only slow aging and extend life if autophagy is functional. It is at present reasonable to conclude that autophagy is an important portion of the way in which the operation of metabolism steers the outcome of aging, but data resulting from the practice of calorie restriction in humans strongly suggests that the magnitude of the benefits that would result from therapeutic upregulation of autophagy just isn't as large as we'd all like it to be - though perhaps the upregulation just needs to be larger. We shall see in the years ahead, as biotech startups such as Selphagy Therapeutics make progress on clinical development of this class of therapy.

Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk

Autophagy is an evolutionarily conserved bulk cellular degradation system that functions to breakdown and recycle a wide array of cytoplasmic components from lipids, proteins, and inclusion bodies, to whole organelles (e.g. mitochondria). Importantly a reduction in autophagic flux (the rate at which autophagosomes form and breakdown cellular contents) is associated with increasing age in mammals. Evidence from lower organisms suggests that autophagy inhibition can negate the positive-effects of regimens that extend lifespan, such as calorie restriction, rapamycin supplementation, and mutations in insulin signalling pathways.

In mice, the constitutive promotion of autophagy throughout lifetime has been shown to extend health- and life-span in mammalian models. These studies have provided hitherto missing evidence that autophagic flux can impact on mammalian longevity and supports the notion that the pharmacological promotion of autophagy may extend health-, and potentially life-span, in humans. However, whether a reduction in autophagy is sufficient to induce phenotypes associated with ageing, and whether these effects can be reversed by restoring autophagy has to date not been addressed. Considering that the therapeutic window for pharmacological intervention to counteract ageing, and age-related diseases, will be later in life (as opposed to from conception), after autophagic flux has declined, it is critical to understand how the temporal modulation (inhibition and restoration) of autophagy may impact on longevity and health.

To address these questions, we use two doxycycline (dox) inducible shRNA mouse models that target the essential autophagy gene Atg5 to demonstrate that autophagy inhibition in young adult mice is able to drive the development of ageing-like phenotypes and reduce longevity. Importantly we confirm that the restoration of autophagy is associated with a substantial restoration of health- and life-span, however this recovery is incomplete. Notably the degree of recovery is segmental, being dependent on both the tissue and metric analysed. A striking consequence of this incomplete restoration is that autophagy restored mice succumb to spontaneous tumour formation earlier and at an increased frequency than control mice, a phenotype not observed during autophagy inhibition alone. As such our studies indicate that despite the significant benefit, autophagy reactivation may also promote tumorigenesis in advanced ageing context.

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