Autophagy Rewrites the Rules of Aging, Cell by Cell

For decades, one of the most repeated mantras in the biology of aging has been deceptively simple: as we grow older, our cells become worse at taking out the trash. That trash-removal process, known as autophagy, is the cellular machinery that sweeps up misfolded proteins, damaged organelles and other molecular debris, seals them inside membrane-bound containers, and digests them back into their basic building blocks for reuse. When autophagy falters, waste accumulates, cells deteriorate, and the stage is set for many of the diseases that shadow old age, from cancer and cardiovascular disease to diabetes and neurodegeneration. Now, a new study from scientists at Sanford Burnham Prebys Medical Discovery Institute, published on September 27, 2026, in the journal Aging Cell, is forcing researchers to rethink that tidy narrative. The findings reveal that autophagy does not simply wind down with age. Instead, its behavior shifts in ways that depend on the type of cell being examined and, remarkably, on the sex of the person the cells came from.

The motivation behind the study grew out of a frustration that many researchers in the field have quietly voiced. Although the claim that autophagy declines with age appears constantly in review articles and grant applications, the direct evidence for that decline in humans is surprisingly sparse. Most of what scientists know comes from model organisms such as yeast, worms, flies and mice, whose cellular recycling systems do not always map cleanly onto human biology. Caroline Kumsta, PhD, assistant professor in the Center for Cardiovascular and Muscular Diseases at Sanford Burnham Prebys and senior and corresponding author of the new paper, put the problem bluntly. People commonly cite the idea that autophagy declines with age, she noted, but the actual evidence for this in humans is very thin. That gap between assumption and data is more than an academic quibble. Interest is growing in targeting autophagy to develop new interventions for healthy aging, and Tatiana Moreno, PhD, lead author of the study and a former graduate student in the Kumsta lab, explained that the team wanted to challenge assumptions and investigate what actually happens to autophagy during aging in healthy individuals.

To do so, the researchers designed an unusually comprehensive experiment using samples from human volunteers aged 23 to 72 who self-reported having no chronic diseases. From each participant, the team collected skin and blood samples, giving them access to cells that represent very different biological neighborhoods within the same body. They then expanded the repertoire of cell types even further by reprogramming skin cells into induced neurons, specialized cells that resemble the neurons of the nervous system and that would otherwise be impossible to obtain directly from living volunteers. This reprogramming technique, which earned its pioneers a Nobel Prize, allowed the investigators to ask how the aging process plays out in a cell type that is central to cognition and movement, without requiring a brain biopsy.

With these cells in hand, the team deployed two complementary measurement strategies, and the contrast between them turned out to be one of the most important technical lessons of the study. First, they sequenced RNA transcripts, the molecular intermediaries created when DNA is read out to produce proteins, enzymes and other cellular machinery. Transcript levels of autophagy genes provide a snapshot of how strongly the recycling program is being expressed. Second, and more tellingly, the researchers used a technique to directly measure the rate of autophagy itself, the actual flux of material moving through the recycling pathway, rather than inferring it from gene activity. Comparing the two measures across dozens of donors revealed a disconnect that has major implications for how autophagy research is conducted. Higher or lower expression of autophagy genes was not correlated with the direct measurement of how fast cells were actually recycling their contents. Moreno cautioned that people using static measures such as transcription levels to infer what is happening with autophagy need to be really careful about their interpretations, a warning that could ripple through a field that has long relied on gene expression as a proxy for flux.

The direct measurements delivered the study’s headline surprise. Autophagic activity, the team found, was not universal across the body and did not follow the idea that cellular recycling simply declines with age. In male skin cells, autophagy did decline with advancing age, consistent with the classical view. In female skin cells, however, it remained stable across the decades sampled. Most striking of all, autophagy increased with age in female induced neurons, a result that inverts the expected pattern entirely. Kumsta summarized the finding by noting that cellular recycling rates are altered differently with age in each of the cell types, and differently by sex in each of the cell types. In other words, there is no single aging curve for autophagy. There are instead a family of curves, each shaped by the tissue in which a cell lives and by the biological sex of the person it came from, and any therapy designed to boost or suppress the pathway will need to reckon with that heterogeneity.

The study then pushed into territory that few autophagy experiments have explored: the relationship between cellular recycling and physical function in living people. If autophagy is genuinely a pillar of healthy aging, one might expect that higher recycling activity would track with better strength, fitness and mobility. The data told a more unsettling story. Among adults aged 70 and older, higher autophagy was associated with poorer physical function across all three cell types examined. The specific associations varied by cell type in ways that hint at distinct underlying biology. Increased autophagic activity in blood cells was associated with decreased aerobic fitness. In skin cells, higher autophagy was linked to a higher body mass index. In induced neurons, elevated recycling tracked with lower grip strength and metabolism and a higher resting heart rate. Taken together, these correlations suggest that in older adults, a revved-up autophagy pathway may be a signal of cellular stress or damage rather than a marker of resilience.

Kumsta argued that this distinction merits continued study, because it appears that increased autophagy flux may be good in younger people yet problematic in older people. That possibility reframes a central assumption of the healthy-aging field. Many proposed interventions, from fasting mimetics to experimental drugs, aim to stimulate autophagy on the theory that more recycling is always better. The new data raise the prospect that the optimal level of autophagic activity changes across the lifespan, and that indiscriminately boosting the pathway in older individuals could backfire. Moreno emphasized that autophagy and aging are far more nuanced than previously assumed, and that translating discoveries into potential therapies will require understanding what is happening at a cell-specific level and how it is affected by both sex and age. For a field that has often treated autophagy as a single dial to be turned up, the message is that the dial reads differently in every tissue.

Amid the caution, the study also delivered a genuinely hopeful result. In a pilot test of one potential future intervention, the researchers examined whether exercise could reshape autophagic activity in older adults. Five participants aged 77 to 88 provided blood samples before and after completing a 12-week mild exercise program focused on preventing falls. The results suggest that exercise may reduce blood cell autophagic activity to match more youthful levels while simultaneously improving physical performance. The finding is intriguing precisely because it runs counter to the intuition that more autophagy is the goal. If elevated recycling in older blood cells reflects stress, then nudging it back down toward a youthful baseline, while improving fitness and function, may be exactly the kind of recalibration that healthy aging requires. Kumsta described the result as exciting, noting that the exercise intervention may have a positive effect on autophagy and healthy aging, and that she is eager to see where it leads.

That excitement is now being converted into a larger research program. The Kumsta lab received a pilot grant from the Altman Clinical and Translational Research Institute at the University of California San Diego to expand the work on exercise, aging, autophagy and physical function, and larger studies with more participants and improved testing protocols are underway in collaboration with the Exercise and Physical Activity Resource Center at UC San Diego. The original study was supported by the National Institutes of Health, the National Cancer Institute, the National Institute on Aging, the American Foundation for Aging Research, the Conrad Prebys Foundation, The Howard and Maryam Newman Family Foundation and the Leona M. and Harry B. Helmsley Charitable Trust, with additional contributions from co-authors at Sanford Burnham Prebys and UC San Diego spanning genomics, induced pluripotent stem cell technology and geriatric medicine. The authors declare no competing interests.

What emerges from the work is a picture of cellular aging that is messier, more individualized and ultimately more tractable than the old decline narrative allowed. Autophagy is not a single switch that dims with time. It is a dynamic, tissue-specific, sex-specific system whose activity can rise, fall or hold steady depending on where in the body one looks and who the cells belong to. Measuring it properly requires direct flux assays rather than shortcuts through gene expression, and interpreting it requires knowing the age and context of the person being measured. If the early exercise results hold up in larger trials, the study may point toward a future in which aging interventions are tuned to restore youthful patterns of cellular recycling rather than simply maximize them. For now, the study stands as a reminder that one of biology’s most fundamental housekeeping processes still has plenty of surprises left in storage, and that the path to healthy aging may run through the trash, one cell type at a time.

Subject of Research: Age- and sex-specific changes in autophagy flux across human cell types and their link to physical function and exercise

Article Title: Cellular recycling changes with age, but not how we expected

Article References: Cellular recycling changes with age, but not how we expected. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: autophagy, aging, cellular recycling, Aging Cell, Sanford Burnham Prebys, induced neurons, gene expression, physical function, exercise intervention, sex differences, healthy aging, blood cells