Autophagy and longevity: Evolutionary hints from hyper-longevous mammals
Andrea G. Locatelli and Simone Cenci
Additional article information
Abstract
Autophagy is a fundamental multi-tasking adaptive cellular degradation and recycling strategy. Following its causal implication in age-related decline, autophagy is currently among the most broadly studied and challenged mechanisms within aging research. Thanks to these efforts, new cellular nodes interconnected with this phylogenetically ancestral pathway and unexpected roles of autophagy-associated genetic products are unveiled daily, yet the history of functional adaptations of autophagy along its evolutive trail is poorly understood and documented. Autophagy is traditionally studied in canonical and research-wise convenient model organisms such as yeast and mice. However, unconventional animal models endowed with extended longevity and exemption from age-related diseases offer a privileged perspective to inquire into the role of autophagy in the evolution of longevity. In this mini review we retrace the appearance and functions evolved by autophagy in eukaryotic cells and its protective contribution in the pathophysiology of aging.
Full paper, open access
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9807614/
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Good overview of scientific efforts at selectively increasing autophagy:
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An interesting new paper from Tim Sargeant’s group in Australia:
Autophagy across tissues of aging mice
Julian M Carosi, Alexis Martin, Leanne K Hein, Sofia Hassiotis, Kathryn J Hattersley, Celia Fourrier, Julien Bensalem and Timothy J Sargeant
Autophagy is a waste-disposal pathway that protects against age-related pathology. It is widely accepted that autophagy declines with age, yet role that sex and diet-related obesity play during aging remain unknown. Here, we present the most comprehensive in vivo study of autophagic flux to date. We employed transgenic mice overexpressing tandem-florescent LC3B (RFP-GFP-LC3B) to measure autophagic flux in the blood (PBMCs), heart, and motor cortex of aging mice that were fed regular chow or a high-fat diet for 6-, 12- or 18-months. In male mice, aging reduced autophagic flux in the heart and brain, but increased it in the blood. Age-dependent changes in female autophagic flux was less pronounced. Autophagic flux was modified by a high-fat diet in the blood and heart of male but not female mice. Overall, we uncovered sexual dimorphisms that underpin how autophagy changes with age across different tissues and in response to a high-fat diet.
bioRxiv. posted 11 September 2024, 10.1101/2024.09.11.612427
http://biorxiv.org/content/early/2024/09/11/2024.09.11.612427
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Tim Sergeant and his research team is moving forward on identifying the levels of autophagy activators; here comparing intermittent fasting vs. caloric restriction. I hope they do rapamycin soon too, so we have some basis of comparison.
Open Access Paper:
Intermittent time-restricted eating may increase autophagic flux in humans: an exploratory analysis
Autophagy slows age-related pathologies and is stimulated by nutrient restriction in animal studies. However, this has never been shown in humans. We measured autophagy using a physiologically relevant measure of autophagic flux (flux of MAP1LC3B isoform II/LC3B-II in peripheral blood mononuclear cells in the context of whole blood) in 121 humans with obesity who were randomised to standard care (SC, control condition), calorie restriction (CR) or intermittent fasting plus time-restricted eating (iTRE) for 6 months. While the differences in change from baseline between groups was not significant at 2 months, we observed a significant difference in change from baseline between iTRE compared to SC at 6 months (P = 0.04, post hoc analysis). This effect may be driven partly by a tendency for autophagy to decrease in the SC group. The difference in change from baseline between CR and SC was not significant. Uncorrected analysis of correlations showed a negative relationship between change in autophagy and change in blood triglycerides. Data on the specificity and performance of the methods used to measure human autophagy are also presented. This shows autophagy may be increased by intermittent nutrient restriction in humans. If so, this is a demonstration that nutrient restriction can be used to improve a primary hallmark of biological ageing and provides a mechanism for how fasting could delay the onset of age-related disease.
Key points
- Autophagy slows biological ageing, and dysfunction of autophagy has been implicated in age-related disease – an effective way of increasing autophagy in cells and animal models is nutrient restriction.
- However, the impact of different types of nutrient restriction on physiological autophagic flux in humans has not been extensively researched.
- Here we measure the effect of intermittent time-restricted eating (iTRE) and calorie restriction on physiological autophagic flux in peripheral blood mononuclear cells.
- After 6 months, there was a significant difference in change from baseline between the iTRE and the standard care control group, with flux being higher in the iTRE group at this timepoint.
- However, there was no significant increase from baseline within the iTRE group, showing that although autophagy may be modified by nutrient restriction in humans, further studies are required.
https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP287938
Interesting comment:
Source: https://x.com/TimSargeant1/status/1921007958579630401
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and Tim responds to my request to look at rapamycin and autophagy:
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and… more in the discussion thread:
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Nick1
#29
That’s very interesting and seems to challenge the fundamental belief or proof of Rapa inducing autophagy!
IF promoting autoaphagy as opposed to CR is not surprising.
May be best to continue to adhere to fasting on the first day of Rapa doing and then continue with IF.
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IF in mice equals extended water fasting in humans. Not ideal for muscle preservation.
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Nick1
#31
True that! But didnt realize fasting equivalence between mouse and human.
I have been down the Prolonged Water fast road. Muscles do pay heavy toll specially of one is in golden decades!
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This is what makes Rapamycin Longevity Lab’s 601 mTOR inhibitor screening with Ora Biomedical’s Million Molecule Challenge so exciting. They’re looking for a better Rapamycin.
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I find the title of this 2025 study — “Intermittent time-restricted eating may increase autophagic flux in humans” — quite misleading. It gives the impression that the study isolates the effect of intermittent fasting or time-restricted eating (TRE). But it doesn’t.
In reality, the study compares two forms of calorie restriction:
- One group followed daily calorie restriction (CR),
- The other followed the same calorie restriction, but limited eating to a 4-hour window on 4 days per week (iTRE).
So this is not a study of intermittent fasting vs calorie restriction — it’s calorie restriction with or without a time window.
For those practicing iso-caloric time-restricted eating (same calories, just in a shorter window), this study says nothing about whether that timing alone has benefits.
It’s a good reminder: always look beyond the headline or title.
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