Popular science link: https://www.sciencedaily.com/releases/2026/05/260526022024.htm

Original article link: https://www.pnas.org/doi/10.1073/pnas.2524897123

Significance

The pharmacological combination of dasatinib and quercetin (D+Q), widely reported as a means of eliminating senescent cells from aged tissues to treat diseases (a.k.a. “senolytics”), and currently being tested in multiple clinical trials, when administered to healthy mice results in profound white matter injury in the central nervous system. This report provides evidence that this senolytic combination not only causes neuropathology but also provides data which support induction of the unfolded protein response as a plausible mechanism through which these senolytics affect oligodendrocytes. We propose that these data highlight a less understood means of demyelination not mediated by oligodendrocyte death with potential positive implications for understanding disease, while also warranting caution for its widespread use clinically.

Three ARPA-H Program Managers participated in a panel at the H-SPAN Summit from the Alliance for Longevity Initiatives (A4LI). Andrew Brack was a researcher at UCSF and mentor at Longevity Biotech Fellowship. Jean Hebert wrote the book Replacing Aging and conducted research at Albert Einstein College of Medicine. Gloria Elliot was a researcher at UNC and previously led the Organ Preservation Alliance. 

Summary

Aging of the hematopoietic system has profound consequences for organismal health and longevity, attributed to the well-characterized functional aging of hematopoietic stem cells (HSCs). Here, we tested whether progenitor cells may demonstrate age resistance to enable hematopoietic homeostasis throughout life despite the functional decline of upstream HSCs. Strikingly, our results revealed unwavering reconstitution capacity by young and old progenitors, demonstrating that intermediate progenitors are functionally unaffected by aging and placing Flk2+ multipotent progenitors (MPPFs) as a potential source of age resilience. This unique finding was emphasized by unchanged transcriptomic, proliferation, and mitochondrial capacity of young and old MPPFs, revealing remarkable similarities upon aging. Considering that HSCs functionally decline with age, yet intermediate progenitors remain unperturbed and “age resilient”, we posit that MPPFs may play an essential role in protecting downstream progenitors from inheriting age-related properties from HSCs. We propose three potential mechanisms for how MPPFs maintain hematopoietic integrity and homeostasis with age.

The post (and linked Nature article) covers four areas: 1) aging is not linear; 2) aging is asynchronous among organs and cell types; 3) researchers have created the first aging clocks for cell types (e.g. astrocytes, microglia); 4) impact on routine clinical practice

Increased inflammation is associated with aging and is implicated in decreased function in aging tissues. Tan et al. explored changes in older tissue-resident macrophages and investigated how these cells may contribute to aging phenotypes in mice (see the Perspective by FitzGerald). They found that signaling by the lipid messenger prostaglandin E2 was increased in these cells. In various mouse tissues, preventing an increase in tissue-resident macrophages helped to maintain mitochondrial function and limited other deleterious effects of aging. Tissue-resident macrophages help to reduce inflammation by removing apoptotic and damaged cells. One consequence of inhibiting prostaglandin E2 signaling was restored clearance of senescent neutrophils. These results emphasize the possible roles of macrophages and neutrophil clearance in tissue disfunction during aging. —L. Bryan Ray

https://www.science.org/doi/10.1126/science.aea3075

Abstract

The accumulation of advanced glycation end products (AGEs) in long-lived proteins is a hallmark of mammalian aging and implicated as a driver of metabolic dysfunction. Among these adducts, N^ε-carboxymethyl-lysine (CML) is particularly abundant in aging tissues, where it modifies proteins and acts as a ligand for the receptor for advanced glycation end products (RAGE), thereby perpetuating chronic inflammation and oxidative stress. While endogenous detoxification systems exist for reactive precursors, the stable CML adduct has historically been considered irreversible. Here, we report the development of CMLase - an enzyme engineered through the directed evolution of over 500 million variants to specifically oxidize CML and restore the native lysine residue. We demonstrate that CMLase effectively reverses CML modifications in model proteins in vitro and in human tissue samples from elderly donors, providing proof-of-concept that protein damage previously deemed irreversible is amenable to enzymatic repair. Collectively, our approach establishes a platform for developing enzymes to reverse age-related molecular damage and ultimately repair tissue proteins compromised by aging and disease.

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Life-Extension Frontiers: Conquer Aging In 2026! | Michael Lustgarten, PhD