One Broken Pathway Drives Aging. Scientists Aim to Fix It

Every cell in the human body has a mini recycling crew. Its job is to hunt down damaged proteins, escort them to a recycling center (lysosome), and thread them one at a time through a molecular pore for destruction. The process is called chaperone-mediated autophagy (CMA), and it happens in every tissue, every day.Until it doesn’t.Ana Maria Cuervo, MD, PhDAs you get older, this process slows down. Damaged proteins build up, and the conditions for disease take root. The researcher who discovered the system — Ana Maria Cuervo, MD, PhD, a distinguished professor of developmental and molecular biology at the Albert Einstein College of Medicine in Bronx, New York — has spent three decades tracing the consequences of its failure across nearly every organ, linking it to age-related conditions such as Alzheimer’s disease, Parkinson’s disease, sarcopenia (muscle loss), vision loss, and immune dysfunction.Now Cuervo and her collaborators are finally developing drugs that target it.Einstein recently launched BIO-VITAL, which is not only an impressive backronym (it stands for the Batia and Idan Ofer program for Validation of Interventions Targeting Aging and Longevity) but also a preclinical platform for compounds targeting CMA and other drivers of aging. Because aging is not recognized as a treatable condition, these drugs must be developed for specific diseases.“CMA has two purposes,” said Cuervo, who directs BIO-VITAL’s cellular aging and technology core. “The first is cleaning — anything that is damaged inside your cell is eliminated. The second is helping to regulate many functions inside the cell, like energy production, because the ones doing all the work inside cells are proteins, and CMA plays with their levels.”One Pathway, Many DiseasesThose two functions explain CMA’s powerful effect on age-related decline. Cuervo’s research, as documented in a systematic atlas published in Nature Aging in 2025, showed drop-offs across the brain, retina, liver, kidney, heart, muscle tissue, and immune tissue in aging mice. Male mice lost CMA faster than female mice, possibly because the gene encoding CMA’s rate-limiting receptor (LAMP2A) sits on the X chromosome. This could explain known sex differences in age-related disease.In a cell with active CMA, lysosomes (represented by the bright fluorescent orange yellow puncta) degrade damaged proteins one at a time. The number and brightness of these puncta decline with age.Studies from Cuervo’s lab have linked CMA failure to processes underlying neurodegenerative disease, such as the buildup of tau and amyloid-beta in Alzheimer’s disease and the aggregation of alpha-synuclein in Parkinson’s disease. CMA’s decline also affects photoreceptor loss in retinal degeneration, SERCA misfolding and sarcomere collapse in sarcopenia, and regulatory T-cell dysfunction in chronic inflammation.In each case, eliminating CMA in young mice reproduced hallmarks of the disease and restoring CMA (either genetically or with small-molecule compounds) reversed or prevented the damage.A mouse brain with intact CMA (left) shows little amyloid-beta and phosphorylated tau, whereas one with no CMA (right) shows widespread accumulation of both proteins, hallmarks of Alzheimer’s disease.But what surprised Cuervo were the findings in older mice: The benefits of restored CMA extended far beyond one pathway. The proteasome — the cell’s other major protein-disposal system — ran more smoothly. Macroautophagy, the bulk recycling process that clears larger cellular debris, improved. Even the chaperone proteins that shuttle damaged molecules to disposal sites became more effective.“In a clean house,” Cuervo said, “things start working better.”One Switch, Two Ways to Flip ItTo create the small molecules used in those rescue experiments, Cuervo teamed up with Evripidis Gavathiotis, PhD, a professor of biochemistry and medicine at Einstein. The drugs target a specific protein complex in the nucleus (the cell’s command center) formed by two molecules: the retinoic acid receptor-alpha (RAR-alpha) and its binding partner NCoR1.Evripidis Gavathiotis, PhDThat complex is CMA’s “on switch.” As long as it’s intact, CMA genes remain active.Gavathiotis designed the compounds to stabilize the interaction, holding the switch in the “on” position so CMA stays active with age.He then designed a compound that does the opposite.In a 2025 paper, Gavathiotis and Cuervo reported a selective CMA inhibitor (CIM7) that disrupts the complex, freeing RAR-alpha to repress CMA genes. CMA levels go down, and cancer cells — which depend on higher CMA levels — die.How’s that for a twist? Targeting the same molecular switch could yield both a neuroprotective drug and an anticancer drug — depending on which direction you flip it.But the cancer story turned out to be more complicated. In healthy cells, CMA acts as a defense — mice engineered to maintain CMA suppressed tumor formation. Once a cell transforms, however, tumors upregulate CMA and use it to fuel their metabolism. When Cuervo’s team eliminated CMA in cancer cells, the cells died.That raised an unsettling question: If you give a CMA activator to an older patient, could you feed an undetected tumor? The answer, at least in mice, appears to be no. When the researchers activated CMA in older mice with premalignant lesions, the tumors did not benefit from it — the immune system did.“If you enhance CMA, the beneficial effect on the immune system is so high that the immune cells of these old mice are able to kill the cancer cells, even if you are activating autophagy in the whole system,” Cuervo said.The Path to PatientsIf the compounds reach clinical testing, the team’s intended first target is dry age-related macular degeneration (AMD), which accounts for 90% of AMD cases and has no approved treatment. An intravitreal injection would deliver the drug directly to the eye, allowing researchers to evaluate safety while measuring vision improvement in a phase 1 trial. Einstein is looking for a commercial partner to fund the path to human studies.In a healthy cell (left), chaperone proteins (red) escort damaged proteins (green) to the lysosome, where LAMP2A receptors (blue) break them down into recyclable amino acids. In aging and disease (right), LAMP2A receptors decline and damaged proteins — such as LRRK2 — accumulate and form toxic aggregates.These are not the only compounds targeting cellular cleanup in aging. Two other drugs that restore broader lysosomal function — Retro Biosciences’ RTR242 and Lysoway Therapeutics’ LW-1017 — entered phase 1 trials in Australia in late 2025 and mid-2026, both targeting Alzheimer’s and Parkinson’s diseases.Neither drug targets CMA, but the progression of both to human trials reflects growing confidence that restoring the cell’s waste-clearing machinery is a viable strategy for diseases of aging.Beyond Cellular AutophagyCuervo’s core also tests drugs aimed at proteostasis, cellular senescence, and mitochondrial function. An adjacent preclinical core runs healthspan assays in animals to test antiaging compounds. The program is directed by Nir Barzilai, MD, professor of medicine and genetics at Einstein and one of the architects of geroscience — a field that sees aging itself as the primary target.“We want to treat your health rather than your disease,” Barzilai said. “That’s our evolution.”Barzilai’s team looks at whether a drug can treat not just a single disease but also the underlying biology of aging itself. The program has already partnered with four biotech companies to evaluate compounds including senolytics, mitochondrial therapeutics, a novel rapamycin analogue, and an orally bioavailable molecule targeting energy homeostasis and neuroinflammation. One partnership is providing second-species preclinical data with an eye toward first-in-human trials in 2027. By partnering with companies to run these kinds of standardized tests, BIO-VITAL is filling a long-standing void in longevity research, which historically has lacked a contract research organization, making results from different companies impossible to compare.The federal government is taking notice. BIO-VITAL runs preclinical testing for two of the teams funded through ARPA-H’s $144 million health longevity program — the largest US investment in gerotherapeutic development to date — and helped design its standardized protocols.David Rubinsztein, FRS, FMedSciDavid Rubinsztein, FRS, FMedSci, is a professor of molecular neurogenetics and a group leader at the UK DRI at Cambridge. He has spent decades developing autophagy-based strategies for neurodegeneration, though his work targets macroautophagy (not CMA). He called the Einstein group’s data “compelling” and its strategy “rational” — but the challenge for any drug targeting the brain is proving it can reach the right tissue at a high enough concentration.There is no way to directly measure whether a CMA-modulating drug is working in a living human brain — unlike antiamyloid antibodies, which PET scans show can clear plaque. CMA’s challenges — target engagement, long-term safety, and clinical trial design — are not unique, Rubinsztein said. Every neurodegeneration approach faces the same obstacles.“This is like the statin problem,” Rubinsztein said. “When I was young, people started taking statins, and all the papers said, ‘It’s reducing cholesterol but not affecting the primary endpoint’” — meaning it hadn’t yet been proven to reduce heart attacks. “That [benefit] became clear after people took statins for enough years. I think we’re going to need the same patience with neurodegenerative disease.”A New Way to AgeCuervo, who trained as a geriatrician in an era where the field’s primary role was managing decline in older adults — keeping them comfortable because the biology of aging was considered immutable — sees the dawn of a new way to age.“We don’t want to eliminate aging…aging is one more stage in life, and it should be a great time,” Cuervo said. “The only thing that prevents you from enjoying it is that you don’t function well and you’re more prone to disease. We can change that.”The proof, she said, is already walking among us. “If there are people who can live to a hundred with that functionality because they have good genetics, we just have to figure out what those genetics are providing — better autophagy, better mitochondria, [and] better function. And if they have it, we can mimic it.”Barzilai remembers when none of this seemed possible. “When I came to aging, I was a freak,” he said. “Nobody wanted to listen to me. It was hard to get money.” Two decades later, the field he helped build has federal funding, bipartisan Congressional support, and a growing pipeline of compounds entering human trials. “People are on the bandwagon now.”Cuervo and Gavathiotis reported holding patents related to CMA-activating compounds (US patent US9512092). Gavathiotis reported having consulting relationships with companies working in cancer therapeutics unrelated to CMA technology. Rubinsztein reported serving as a consultant with Drishti Discoveries, PAQ Therapeutics, MindRank AI, Retro Biosciences, Alexion Pharma International Operations, Carlyle Investment Management, Aladdin Healthcare Technologies, Nido Biosciences, and ProtOS Bio and being a co-founder of Acuity Technologies. Barzilai reported having no relevant financial disclosures.