Considering Autophagy in Long-Lived Species

To what degree is autophagy important in the sizable differences in life span between mammalian species? That is an interesting question. It appears that long-lived species exhibit more effective autophagy, and it also appears that many of the methods of altering metabolism in order to modestly slow aging that were discovered over the past thirty years involve upregulation of autophagy. The effects of calorie restriction on longevity depend upon the correct function of autophagy, and vanish if autophagy is disabled.

It is worth noting that autophagy is difficult to measure, however. It involves many distinct processes, such as identification of materials for recycling, formation and transport of autophagosomes, the operation of lysosomes, and so forth. One can measure the activity of specific proteins involved in various steps of autophagy, but that isn't necessarily informative as to whether the whole autophagic system is functioning correctly.

Further, calorie restriction may extend life in mice by up to 40%, but it certainly doesn't do anywhere near as much in long-lived mammalian species such as our own. Can autophagy really be so great a contribution to species differences in life span if calorie restriction and consequent upregulation of autophagy only adds a few years to human life span? It is hard to reconcile that with the difference between a rat life span of a few years and a naked mole-rat life span of a few decades, or the sizable difference in life span between a human and the longest-lived whales.

Autophagy and longevity: Evolutionary hints from hyper-longevous mammals

The decline of autophagic ability is one of the most acknowledged molecular hallmarks of cellular aging. As eukaryotic organisms age, they suffer from a progressive, maladaptive decrease in the ability to activate autophagy and benefit from its degradative/renewal properties, leading the cells to accumulate damaged organelles and cytotoxic macromolecules overall. Autophagy appears to be intimately connected with the modulation of longevity, as proved by several studies which demonstrated an effect on cellular and organismal lifespan when autophagy was harnessed either genetically or pharmacologically. The exact mechanisms behind this connection are yet unclear, given the vastity of genes involved in the process and the different function afforded by autophagy including proteostasis, nutrient regulation, and immunity.

Evolution provides us with evidence of selective adaptations in the autophagic process across long-lived organisms, including phylogenetically close-to-humans taxa belonging to the mammalian clade. This confirms the existence of an either direct or indirect link between autophagy and lifespan modulation but concurrently may represent a unique opportunity to shed light on the key molecular elements involved through comparative studies. A connection between autophagic activity and organismal lifespan was first identified in a pioneering study on insulin/IGF-1 signalling, where autophagy-inducing mutations in daf-2 were associated with lifespan extension in C. elegans and later confirmed in organisms such as drosophila, mice, and humans. Another important discovery linking autophagy with longevity emerged from studies on mTOR signalling and dietary restriction, an established universal life-extending intervention. Starvation-induced autophagy was proven to be causal to lifespan extension in several animal models from yeasts to great apes.

Transcriptomic studies of the longest-lived mammal, the bowhead whale (Balaena mysticetus), revealed overexpression of genes for DNA repair, autophagy induction, and ubiquitination. To better inquire into the evolution of longevity in mammals, further studies were aimed towards the identification of unique adaptations in molecular markers of aging in taxa characterised by high longevity quotients. One of the most studied mammalian species characterised by a high longevity quotient is the naked mole rat (NMR, Heterocephalus glaber). This rodent is capable of living substantially more than expected more for a mammal of comparable body size. Interestingly, studies of the NMR showed higher basal autophagic activity (measured as expression of LC3II and beclin-1 autophagic marker proteins) when compared with C57Bl/6 mice. Furthermore, NMR's transcriptome analyses recapitulated features found in the bowhead whale, with overexpression of genes for DNA repair and autophagy, which proved down-regulated in mammals with low longevity quotients, such as mice and cattle.

A study on the speciation of another noncanonical rodent model characterized by a high longevity quotient, the blind mole rat (Spalax galili), revealed a strong dependence on proteostatic machineries such as autophagy and the proteasome in determining niche adaptation, since these animals need to deal with a high metabolic stress deriving from the limited nutrient sources of soil dwelling.

Another example of this phenomenon may be the case of the unique evolution witnessed in bats, the order of mammals with the highest longevity quotient among all. During the last years, several studies have been aimed to decipher the exceptional resistance of bats against aging and age-related diseases with many of these reporting an upregulation of autophagic activity across different tissues when compared with mice and other mammals. In a study on primary fibroblasts, both young and aged bats were found to have a constitutively higher level of autophagic flux than murine counterparts. Further analyses on the blood transcriptome showed upregulation of autophagy-associated genes and transcript enrichment for terms associated with macroautophagy and positive regulation of autophagy. Autophagy in bats arguably evolved to face the massive production of cytotoxic metabolic by-products deriving from the extremely energetically demanding activity of powered flight.

Finally, being aging now acknowledged as the driving cause of all age-related disorders, worth of interest are the evolutionary implications deriving from evidence of resistance from these diseases in the longest-lived mammalian models. Further attesting to autophagy as an anti-aging biological asset, recent studies found high autophagic activity to inversely correlate with the incidence and severity of pathologies associated with aging, such as neurodegeneration, frailty, and cancer. Bats are once again a unique study model as they show high cognitive performances (e.g., echolocation) throughout their extended lifespan, do not display phenotypic aging (young and old bats are macroscopically indistinguishable), and show lower occurrence of cancer when compared with other mammals.


Considering that the humanity was living in constant forced calorie restriction all the way up to 19 or even early 20 century we would have witnessed poor folks living to 150.. well... nowhere to be found.

most probably we can get a few extra years of healthspan with enhanced autophagy. Nothing to scoff at, of course. But that's the best case scenario.

Posted by: Cuberat at January 25th, 2023 2:32 PM

Cuberat: there are a lot of problems with that argument for humans. For starters, we *did* witness such folks living a long time. There are endless thousands of instances of such folks... We just dismiss them all as fraud, error, pious inflation, and so on, because none of them have rigorous state-issued identification and records which could convince us contemporary people; which is doubtlessly correct in the vast majority of cases, but also throws out any baby with the bathwater, so you can't use that to argue that there is no baby. They also had extremely poor nutrition overall; it's not caloric restriction when you're eating the typical peasant diet, it's just starvation and malnutrition. Plus all the other health issues. It's unclear if you should expect any benefit from CR when you're fighting off lifelong health issues from scores of lethal childhood infections combined with malnutrition and heavy labor etc. You would need a situation where a country preceded all its lifestyle changes by a good century and a half of absolutely immaculate fraud-proof record-keeping plus economic growth plus public health interventions like universal vaccination or water treatment plus... etc. Obviously there is nowhere that has happened. Those changes all go together, hopelessly intermixed and interdependent.

Posted by: gwern at January 31st, 2023 1:18 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.