LongeCityNews Last Updated: 02 December 2025 - 11:33 AM

Lysosomes are a vital component in the recycling systems of the cell, organelles that break down harmful or unwanted molecules in order to provide raw materials for manufacture of new molecules. As is the case for all cell components, lysosomes become dysfunctional with age. The buildup of persistent metabolic waste, such as lipofuscin, that cells struggle to break down is implicated in age-related lysosomal dysfunction in long-lived cells, such as neurons. Sweeping epigenetic and transcriptomic changes that alter the production of proteins occur with age in all cells, and it is likely that a subset of these changes contributes meaningfully to impaired lysosomal function.

Today's open access paper is interesting not just for the connection between specific forms of lysosomal dysfunction and hematopoietic stem cell aging, and thus the aging of the immune system, but also because the researchers involved found that a vacuolar ATPase inhibitor can reverse this dysfunction. Vacuolar ATPases are responsible for acidifying lysosomes, among other activities, and the specific issue identified in aged hematopoietic stem cells is that their lysosomes are overly acidic. When lysosomes cease to function efficiently, as appears to happen in this circumstance, the whole cell suffers because harmful molecules are not cleared and recycled in good time. As the researchers point out, this includes mislocalized DNA from mitochondria that can trigger inflammatory pathways. Restoring lysosomal function in aged cells reduces inflammatory signaling and improves cell health.

Scientists Reverse Aging in Blood Stem Cells by Targeting Lysosomal Dysfunction

Lysosomes are specialized structures that act as the cell's recycling system, breaking down proteins, nucleic acids, carbohydrates, and lipids. Lysosomes accumulate and degrade waste, and eventually recycle it to be reused in biosynthetic processes. Lysosomes can also store nutrients to be released when needed. Lysosomes are recognized as pivotal for regulating metabolism in the cell, both catabolism (breaking down complex molecules to simple ones) and anabolism (building complex molecules from simpler ones).

As people age, hematopoietic stem cells (HSCs) become defective and lose their ability to renew and repair the blood system, decreasing the body's ability to fight infections as seen in older adults. Another example is a condition called clonal hematopoiesis; this asymptomatic condition is considered a premalignant state that increases the risk of developing blood cancers and other inflammatory disorders. Its prevalence increases significantly with age.

Researchers discovered that lysosomes in aged HSCs become hyper-acidic, depleted, damaged, and abnormally activated, disrupting the cells' metabolic and epigenetic stability. Using single-cell transcriptomics and stringent functional assays, the researchers found that suppressing this hyperactivation with a specific vacuolar ATPase inhibitor restored lysosomal integrity and blood-forming stem cell function. The old stem cells started acting young and healthy once more. Old stem cells regained their regenerative potential and ability to be transplanted and to produce more healthy stem cells and blood that is balanced in immune cells; they renewed their metabolism and mitochondrial function, improved their epigenome, reduced their inflammation, and stopped sending out "inflammation" signals that can cause damage in the body.

Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells

Aging impairs hematopoietic stem cells (HSCs), driving clonal hematopoiesis, myeloid malignancies, and immune decline. The role of lysosomes in HSC aging - beyond their passive mediation of autophagy - is unclear. We show that lysosomes in aged HSCs are hyperacidic, depleted, damaged, and aberrantly activated. Single-cell transcriptomics and functional analyses reveal that suppression of hyperactivated lysosomes using a vacuolar ATPase (v-ATPase) inhibitor restores lysosomal integrity and metabolic and epigenetic homeostasis in old HSCs. This intervention reduces inflammatory and interferon-driven programs by improving lysosomal processing of mitochondrial DNA and attenuating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling. Strikingly, ex vivo lysosomal inhibition boosts old HSCs' in vivo repopulation capacity by over eightfold and improves their self-renewal. Thus, lysosomal dysfunction emerges as a key driver of HSC aging. Targeting hyperactivated lysosomes reinstates a youthful state in old HSCs, offering a promising strategy to restore hematopoietic function in the elderly.

Many researchers in the United States have finished eating turkey and begun shopping, but their work continues. Here’s what people around the world have been doing to fight aging in November.

Interviews

George Church on Building “Scientific Superintelligence”: This involves creating an array of AI models and building huge robotic labs to quickly test AI-generated hypotheses and feed the data back into the model.

Advocacy and Analysis

If Death Were Optional, Would You Still Choose It?: The idea of living longer, healthier lives thanks to rejuvenation biotechnology has steadily become more common, but the answers to questions about it depends on how they are presented.

The Key Questions of Longevity Research: In GeroScience, a large team of researchers, including João Pedro de Magalhães, has described a hundred currently unsolved problems in the field.

Research Roundup

Skin Aging Underlined by Loss of Capillary Macrophages: A new study ties the disappearance of capillary-associated macrophages to age-related vascular degeneration in the skin.

Rapamycin May Delay Age-Related Fertility Decline: In a recent study, researchers identified that an increase in the expression of ribosome-related genes and a loss of protein homeostasis contribute to the age-related decline in female fertility.

EDA2R May Be an Aging Biomarker and Inflammaging Target: A review in Aging Cell has cataloged the harmful effects of EDA2R, a protein that affects three distinct inflammation-related pathways.

Mice With Reduced Astrocytic Oxidative Stress Live Longer: Directly reducing the production of reactive oxygen species at their source in astrocytes, mitochondrial complex III, improves neuronal health and significantly increases lifespan in a mouse model of Alzheimer’s.

High-Fiber Foods May Fight T Cell Senescence: Researchers have discovered that butyrate, a short-chain fatty acid with well-documented gut benefits, fights senescence in T cells.

New Gene Therapy Robustly Lowers LDL and Triglycerides: A new Phase 1 trial produced encouraging safety and efficacy results for a CRISPR-based gene therapy that silences a gene important for lipid regulation.

Multilingualism Is Associated With Delayed Aging: The protective effect of speaking one foreign language diminished with age, while the protective effect of speaking two or more foreign languages was more robust with aging

NAD+ Rescues Mouse Tauopathy by Fixing Alternative Splicing: A new study reveals a surprising mechanism that might be behind the beneficial effects of NAD+ in preclinical models of Alzheimer’s disease.

A Sarcopenia-Related MicroRNA May Help Pinpoint Its Origin: In Aging Cell, researchers have discovered a potential way to use a microRNA to diagnose sarcopenia, the age-related loss of muscle.

Improved Stem Cells Rejuvenate the Brains of Monkeys: Scientists have genetically modified human mesenchymal progenitor cells to express a more potent version of the “longevity gene” FOXO3, producing rejuvenative effects in monkeys, mice, and human cells.

The Impact of Plant Polyphenols on Ovarian Aging: A recent review in the Journal of Ovarian Research summarizes current knowledge of the impact of various polyphenols on different aspects of ovarian aging.

How Senescent Cells Encourage Melanoma Growth: Researchers publishing in Aging Cell have documented a key reason why older people are much more likely to get melanoma, finding that it is directly attracted to senescent cells.

Nanoparticles Improve Intercellular Mitochondrial Transfer: Scientists have created “nanoflowers” that nudge donor cells to produce more mitochondria, which can then be transferred to recipient cells to boost their mitochondrial function.

Fixing Lysosomes Improves Blood Stem Cell Function: In a recent study, scientists have demonstrated that lysosomal dysfunction actively decreases the potency of hematopoietic stem cells. Calming lysosomes reversed this process, opening avenues for new treatments.

The Roles of Phenylalanine and Tyrosine in Lifespan: Using UK Biobank data, the researchers reported an association between tyrosine and shorter lifespan, with sex-specific differences. The results for phenylalanine were more inconsistent.

An AI-Based System Has Found a Potential Longevity Drug: Prof. Vadim Gladyshev and a team of researchers have used an artificial intelligence-based system to discover a wide variety of potential interventions, including a drug that significantly improves biomarkers of frailty in mice.

A Subtype of T Cells Counters Senescence in Mice: Scientists have discovered that a cytotoxic subtype of CD4 T cells, which is enriched in old people, helps control cellular senescence.

A collagen amino acid composition supplementation reduces biological age in humans and increases health and lifespan in vivo: Oral supplementation in humans demonstrated improved skin features within three months and a reduction in biological age by 1.4 years (p = 0.04) within 6 months.

Body-wide multi-omic counteraction of aging with GLP-1R agonism: These findings have broad implications for the mechanisms behind GLP-1RAs’ pleiotropic benefits, guiding clinical trials, and informing the development of anti-aging-based therapeutics.

NAD+ reverses Alzheimer’s neurological deficits via regulating differential alternative RNA splicing of EVA1C: NAD+ reduces Alzheimer’s pathologies, at least partially, via amplification of the NAD+-EVA1C splicing axis, pointing to a potential splice-switching therapy for Alzheimer’s.

Organ-specific proteomic aging clocks predict disease and longevity across diverse populations: The brain aging clock further stratified Alzheimer’s disease risk across APOE haplotypes, and a super-youthful brain appears to confer resilience to APOE4.

Human Umbilical Cord Plasma Metabolomics Uncover Potential Metabolites for Combating Aging: These findings provide novel insights into the distinctive characteristics of the human cord plasma metabolome and identify promising metabolites with therapeutic potential for antiaging and other cord blood-based medical applications.

Nasal Mucosa-Derived Extracellular Vesicles as a Systemic Antiaging Intervention: These findings support the translational potential of nmEVs as a multifaceted therapeutic candidate for systemic aging intervention.

Low-dose ionizing radiation promotes lifespan extension and stress resistance of C. elegans via DAF-16/SKN-1 mediated adaptive response: This work identifies a critical regulatory network that drives lifespan extension and stress resistance in C. elegans, and provides candidate targets and mechanistic insights for preventive interventions.

Reporting quality, effect sizes, and biases for aging interventions: a methodological appraisal of the DrugAge database: Although anti-aging interventions may have different effects depending on when they are started, most studies began giving the intervention under investigation very early in the organism’s lifespan.

Life-extending interventions do not necessarily result in compression of morbidity: a case example offering a robust statistical approach: This framework offers a valuable tool for future studies, and further refining this method will be crucial to determine under which circumstances lifespan extension leads to morbidity compression.

Targeting RhoA nuclear mechanoactivity rejuvenates aged hematopoietic stem cells: Together, these data outline an intrinsic RhoA-dependent mechanosignaling axis, which can be pharmacologically targeted to restore aged stem cell function.

Anti-uPAR CAR T cells reverse and prevent aging-associated defects in intestinal regeneration and fitness: These findings reveal the deleterious role of uPAR-positive cells on intestinal aging in vivo and provide proof of concept for the potential of targeted immune-based cell therapies to enhance tissue regeneration in aging organisms.

Machine learning predicts lifespan and suggests underlying causes of death in aging C. elegans: Different life-extending treatments result in distinct patterns of suppression of senescent pathology.

REVIVE: a computational platform for systematically identifying rejuvenating chemical and genetic perturbations: When applied to a large-scale in silico screen of more than 10000 compounds and genetic perturbations, REVIVE recapitulates known interventions as well as 477 novel compounds that restore a more youthful transcriptional state.

News Nuggets

Insilico Unveils Portfolio of Unique Cardiometabolic Assets: Insilico Medicine, a clinical-stage drug discovery and development company, announced the launch of its innovative cardiometabolic disease portfolio of unique highly-differentiated molecules discovered using generative AI.

Vincere Biosciences Awarded $5 Million Grant: Vincere Biosciences announced the receipt of a $5 million grant from The Michael J. Fox Foundation for Parkinson’s Research through its Therapeutics Pipeline Program.

As you might be aware, the genetic differences present in Down syndrome patients produce a dramatic acceleration of amyloid-β aggregation, tau aggregation, and the other pathologies of Alzheimer's disease. Researchers here describe the discovery of a variant in the gene CSF2RB in a subset of Down syndrome patients that resist loss of cognitive function, and show that it improves the function of microglia. Microglia are innate immune cells resident in the brain. Increased inflammation and dysfunction in this cell population is strongly implicated in neurodegenerative conditions such as Alzheimer's disease. When equipped with the variant CSF2RB, microglia are less inflammatory and more capable when exposed to Alzheimer's-related protein aggregates - which may be enough to explain the resilience of patients with this gene variant.

Alzheimer's disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer's disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience.

Here, we introduce a myeloid DS-linked CSF2RB A455D mutation into human pluripotent stem cell-derived microglia from both donors with DS and healthy donors and study their function in 4 to 10-month-old chimeric mice. We find that this mutation suppresses type I interferon signaling in response to tau pathology, reducing inflammation while enhancing phagocytosis, thereby ameliorating microglial senescence.

Thus CSF2RB A455D-expressing microglia form a unique protective subpopulation and preserve neuronal functions. Importantly, they replace diseased wild-type microglia after tau exposure. These findings provide proof of concept that engineered human microglia can enhance resilience against tauopathy, opening avenues for microglial replacement therapies.

Link: https://doi.org/10.1038/s41593-025-02117-8

Researchers here point out that inflammatory bowel disease can produce intestinal dysfunction that is in ways similar to the intestinal dysfunction that occurs in aging, but the underlying mechanisms are quite different. It is a good example of the way in which forms of cell and tissue damage can produce dysfunction that appears superficially similar to aging, even when the damage is not the same as occurs during aging. This is true for DNA repair deficiencies that lead to excessive DNA damage, far more than occurs with aging, for example, or for the excessive accumulation of broken lamin A in progeria that doesn't occur to a large degree in normal aging.

Inflammatory bowel disease (IBD) and physiological gut aging present with overlapping clinical features, including impaired barrier functioning, decreased nutrient absorption, and intestinal frailty. Emerging evidence indicates that even young IBD patients can exhibit gut phenotypes akin to those seen with aging. However, the two processes differ substantially in their underlying mechanisms.

Gut aging is characterized by low-grade, chronic inflammation, and gradual cellular senescence, whereas IBD involves persistent immune activation, cyclical tissue damage, and accelerated degenerative changes. This review systematically contrasts physiological gut aging and IBD-associated accelerated gut aging across several dimensions: cellular senescence and programmed cell death, immune cell remodeling, alterations in gut microbiota, changes in mesenteric adipose tissue, and the evolving role of the appendix.

By integrating current advances in basic and translational research, this article highlights both the shared and distinct pathways driving gut dysfunction in aging and IBD, and underscores the importance of early recognition and targeted intervention for premature gut aging in clinical practice.

Link: https://doi.org/10.5582/bst.2025.01279