LongeCityNews Last Updated: 11 December 2025 - 09:04 AM

A number of distinct cellular processes are labeled as forms of autophagy. These are ways in which a cell identifies unwanted structures and molecules, conveys those unwanted structures and molecules to a lysosome, and there breaks down the unwanted structures and molecules into raw materials. Autophagy is necessary for cell function, and has attracted attention in the aging research space for a number of reasons. Firstly the efficiency of autophagy appears to decline with age, secondly a number of ways to alter metabolism to modestly slow aging, such as calorie restriction and mTOR inhibition, appear to primarily function via increased efficiency of autophagy, and thirdly a few strategies to directly and selectively improve the efficiency of autophagy, such as LAMP2A upregulation, have also been shown to slow aging.

Today the focus is on chaperone mediated autophagy, in which unwanted proteins bind to a chaperone protein such as HSC70 that in turn binds to features such as LAMP2A on the surface of a lysosome, allowing the unwanted protein to be engulfed and then broken down. A pair of recently published papers from a team that has been working on LAMP2A for twenty years or so caught my attention. The work implicates an age-related decline in the efficiency of chaperone mediated autophagy in the aging of muscle tissue. The researchers show that maintaining efficient chaperone mediated autophagy in later life, achieved via upregulation of LAMP2A in a genetically engineered mouse lineage, can slow the age-related loss of muscle mass and strength. This approach likely works via helping to maintain muscle stem cell function into later life.

Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy

Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise, and tissue repair, but declines in ageing and obesity.

Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.

Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age

Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration.

Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.

Comparison of human umbilical cord blood with adult plasma revealed hundreds of metabolites whose abundances were age-dependent. Two different formulas, each a mix of a few metabolites, demonstrated anti-senescence properties in cell cultures and model organisms [1].

Young blood has benefits

Previous research has provided evidence that surgically connecting the circulatory systems of young and aged mice, known as parabiosis, in which older animals receive blood from young animals, can lead to reversal of age-associated deterioration in the older animal [2].

Going one step further (or rather, one step younger) is to investigate the properties of human umbilical cord blood and their anti-aging effects, something that has been done by the researchers who just published this study in Aging Cell.

The unique metabolites

Previous studies suggested that human umbilical cord blood has potential applications in anti-aging interventions [3, 4], with some studies showing that human umbilical cord plasma transfusion into aged mice improved their cognitive function [5]. However, no study has compared the metabolite composition of umbilical cord blood and adult blood. Those researchers filled that gap with an analysis of all the metabolites (metabolomics) in human umbilical cord blood, which they compared to adult plasma metabolites.

The researchers recruited 60 mother-offspring pairs with healthy pregnancies and 270 healthy adults, who were divided into groups based on age: young adults (18-25 years), middle-aged individuals (40-55 years), and elderly individuals (65-86 years), and they analyzed the metabolites in their blood. They identified 1092 compounds, with 662 showing significantly different abundances between cord plasma and adult samples.

Further analysis of the identified metabolites revealed 43 molecular pathways that differed between cord plasma and adult plasma, suggesting extensive metabolic changes. Ten of the most differing pathways showed an increase in metabolite abundance in cord plasma. Some of those pathways were linked to amino acid metabolism, biotin metabolism, and pantothenate and CoA biosynthesis, which have been previously shown to positively impact health through their antioxidant properties, promoting wound healing and immune modulation [6-8].

There were 56 metabolites that showed at least a fourfold difference between cord and adult plasma, with 42 of them being more abundant in the cord plasma. Some of those 42 metabolites were also previously reported to have anti-aging properties. One example is inosine, whose antioxidant and anti-inflammatory properties were linked to improvements in learning and memory in aged rats [9]. The 56 metabolites were grouped into nine distinct functional groups, with metabolites that increased or decreased in cord blood forming separate clusters.

Newborn plasma’s anti-aging potential

Previous research suggested that cord plasma metabolites might include some anti-aging properties. Given the apparent differences between cord and adult plasma metabolites, the researchers set out to identify such candidates. They searched for metabolites that were “characterized by significantly higher abundance in cord blood and a declining trend with age progression.” Their analysis yielded 211 potential candidates grouped into 34 distinct pathways, with the most notable related to amino acid metabolism. Some of those metabolites were previously reported to have anti-aging properties; however, many others have not been linked to aging, suggesting potential new approaches and research avenues.

Looking at broader cellular processes, the identified metabolites were grouped into six functional categories: inflammation, oxidative stress, energy and nutrition, proteostasis, DNA damage, and others. The five listed categories are well known to be implicated in aging processes.

To narrow down the list of 211 candidates based on their anti-aging potential, the authors ranked them based on two criteria: “(i) the fold change in abundance between cord and adult plasma, and (ii) the inverse correlation between their abundances and age.” Using those, they created a composite metric for antiaging potential. They identified 42 metabolites that ranked highest on both metrics, making them the most promising candidates. On the flip side, they noted 101 metabolites that had the potential to promote aging, as they were less abundant in cord blood than in adult blood and their levels increased with age.

Validating candidates

The researchers experimentally validated the anti-aging potential of a selected group of metabolites that they identified using cell culture experiments and the model organism C. elegans, a nematode frequently used in aging research. First, they focused on carnosine, taurocholic acid, inosine, L-histidine, and N-acetylneuraminic acid, the five metabolites that ranked highest in their analysis (increased levels in umbilical cord plasma and decline with aging), and they created a formula they refer to as Cord-Formula 1 (CF1).

They treated human embryonic lung fibroblasts with CF1 after first inducing senescence using two different approaches: etoposide treatment, which causes DNA damage, and hydrogen peroxide-induced, oxidative stress-associated senescence. CF1 treatment reduced senescence markers and suppressed the upregulation of senescence-related genes, including SASP genes.

Similar anti-aging effects were seen when the same experiments (induction of senescence in lung fibroblasts) were conducted, but this time the cells were treated with a different formula: Cord Formula 2 (CF2), made of five short peptides. Those short peptides were also identified during the analysis, and their levels were increased in umbilical cord plasma and decreased with age. However, the researchers note that “they have no prior reports of antiaging activity.“

Treating C. elegans with either CF1 or CF2 significantly extended the animals’ lifespan. It also led to reduced markers of aging, improved motor ability (which declines with age), and enhanced stress resistance. There was no negative impact on the animal’s body length or fertility, suggesting a lack of toxicity.

Developing future interventions

Those experiments, while they need to be confirmed in different systems and in humans, provide initial proof-of-concept that some metabolites from the umbilical cord plasma can indeed have anti-senescence and anti-aging activity. What’s more, since those are metabolites that naturally occur in plasma, there shouldn’t be concerns regarding their safety, which should make the development of potential interventions easier and faster.

The authors point out that while their analysis provided insightful new information, there is room for improvement. Metabolite levels have not yet been correlated with people’s broader health and aging profiles. Future studies could increase the number of participants with diverse aging trajectories, ranging from people with comorbidities to centenarians. These studies would allow researchers to assess “whether these metabolites are mere markers of aging or active modulators of healthy aging processes,” how they correlate with various health trajectories, and what kinds of interventions would be most beneficial to populations at different levels of health.

Literature

[1] Liu, J., Jiang, S., Shen, Y., Wang, R., Jin, Z., Cao, Y., Li, J., Liu, Y., Qi, Q., Guo, Y., Wang, Y., Xie, B., Li, J., Cao, A., Wang, Y., Yan, C., Han, Q., Zhu, Y., Peng, J., Dong, F., … Xia, Q. (2025). Human Umbilical Cord Plasma Metabolomics Uncover Potential Metabolites for Combating Aging. Aging cell, e70295. Advance online publication.

[2] Ma, S., Wang, S., Ye, Y., Ren, J., Chen, R., Li, W., Li, J., Zhao, L., Zhao, Q., Sun, G., Jing, Y., Zuo, Y., Xiong, M., Yang, Y., Wang, Q., Lei, J., Sun, S., Long, X., Song, M., Yu, S., … Liu, G. H. (2022). Heterochronic parabiosis induces stem cell revitalization and systemic rejuvenation across aged tissues. Cell stem cell, 29(6), 990–1005.e10.

[3] Mei, Q., Mou, H., Liu, X., & Xiang, W. (2021). Therapeutic Potential of HUMSCs in Female Reproductive Aging. Frontiers in cell and developmental biology, 9, 650003.

[4] Bae, S. H., Jo, A., Park, J. H., Lim, C. W., Choi, Y., Oh, J., Park, J. M., Kong, T., Weissleder, R., Lee, H., & Moon, J. (2019). Bioassay for monitoring the anti-aging effect of cord blood treatment. Theranostics, 9(1), 1–10.

[5] Castellano, J. M., Mosher, K. I., Abbey, R. J., McBride, A. A., James, M. L., Berdnik, D., Shen, J. C., Zou, B., Xie, X. S., Tingle, M., Hinkson, I. V., Angst, M. S., & Wyss-Coray, T. (2017). Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature, 544(7651), 488–492.

[6] Miallot, R., Millet, V., Galland, F., & Naquet, P. (2023). The vitamin B5/coenzyme A axis: A target for immunomodulation?. European journal of immunology, 53(10), e2350435.

[7] Cararo, J. H., Streck, E. L., Schuck, P. F., & Ferreira, G.daC. (2015). Carnosine and Related Peptides: Therapeutic Potential in Age-Related Disorders. Aging and disease, 6(5), 369–379.

[8] Solana-Manrique, C., Sanz, F. J., Martínez-Carrión, G., & Paricio, N. (2022). Antioxidant and Neuroprotective Effects of Carnosine: Therapeutic Implications in Neurodegenerative Diseases. Antioxidants (Basel, Switzerland), 11(5), 848.

[9] Srinivasan, S., Torres, A. G., & Ribas de Pouplana, L. (2021). Inosine in Biology and Disease. Genes, 12(4), 600.

As a brief introduction to the way in which the statistical tools used by policy makers exhibit important disconnections from reality, one can start with the quality-adjusted life year (QALY) and value of statistical life (VSL). Sadly we live in a world in which medicine is ever more centralized and regulated, with an ever greater fraction of decisions made by regulators based on statistics rather than by the individual patient based on their preferences. The paper here is an interesting glance at the relationship between the value of QALY and the VSL as used in practice, in this course of arguing that the value of QALY used in policy decisions should change with age (and other circumstances) because the VSL changes with age (and other circumstances).

In the healthcare sector, cost-benefit analysis (CBA) using measures such as the value of statistical life (VSL) and quality-adjusted life years (QALY) is commonly employed to guide policy interventions and the efficient allocation of healthcare resources. The VSL is calculated based on willingness to pay for mortality risk reduction and is widely used in CBA to evaluate the economic benefits of a policy. The QALY, which considers both quality of life (QoL) and life expectancy, equates one QALY to one year of life in perfect health (QoL = 1).

The VSL and QALY are considered to be closely related, and research on their relationship has been active in recent years. This measure allows for cross-sectional comparisons of different healthcare policies and is widely used in many countries as a standard metric for public health policies and resource allocation decisions. By employing QALY-based CBA, policymakers can quantitatively assess the effectiveness of healthcare interventions based on scientific evidence, thereby facilitating informed decision-making. For instance, the UK's National Institute for Health and Care Excellence (NICE) uses QALY to assess pharmaceutical and medical technologies, providing guidelines for the effective use of limited healthcare resources.

However, the QALY has several limitations. For example, it applies uniformly across different age groups, despite significant differences in health status and life expectancy between younger and older individuals. The current QALY-based CBA may not adequately account for age-specific differences, potentially leading to biased results. Additionally, QALY values are often derived based on practices from other countries without fully considering regional characteristics such as population, economic conditions, and age distribution.

This study aims to present a QALY metric that considers age-specific health status (QoL) and life expectancy by deriving QALY from VSL. We model the VSL-based QALY and demonstrate its effectiveness through a scenario and policy evaluation analysis. In this study, we focus our analysis on the monetary value of a QALY that arises solely from life extension without incorporating QoL improvements and present the results of VSL, QALY, and policy cost reduction, using socioeconomic data from Japan.

Link: https://doi.org/10.1038/s41598-025-29794-6

Stressing cancer cells to induce a senescent state is a secondary goal of cancer therapy, after inducing cell death, as senescence brings a halt to replication. Senescent cell burden is an important component of degenerative aging, and so clearance of the senescent cells created by treatment following the completion of cancer therapy should be beneficial to patients. There is a complex relationship between the presence of senescent cells and the ability of a cancer to grow, however. Senescent cells draw the attention of the immune system, but also secrete signals that can help to support the growth of cancerous cells. There is some debate over whether one should expect clearance of senescent cells during cancer treatment to help or hinder the goal of eliminating the cancer. Here, researchers provide animal model data to suggest that removing senescent cells hinders cancer growth to some degree.

Immunologically mediated clearance of senescent cells has been demonstrated in several model systems. Given increasing evidence for these cells promoting tumor pathology and immune escape, we sought to examine whether a vaccine against senescent cells can lead to tumor regression. A senolytic dendritic cell (DC) immunotherapy ("SenoVax") was created by pulsing DC with cell lysate from senescent fibroblasts, producing DCs that expressed co-stimulatory molecules, stimulated T cell proliferation, and expressed the senescence antigen p16.

SenoVax induced prophylactic and therapeutic tumor regression in Lewis Lung Carcinoma (LLC) primary and metastatic murine tumor models. T cell proliferative and cytokine recall responses towards senescent cells but not to control stromal cell pulsed DCs were detected in vaccinated mice. Additionally, reduction in senescence associated biomarkers IL-11, IL-6, IL-23 receptor, and YLK-40 were observed. Adoptive transfer experiments revealed a role for CD8+ T cells in transplanting protection.

When SenoVax was administered in combination with anti-PD-L1 or anti-CTLA-4 antibodies, the data showed synergistic effects in reducing tumor growth. SenoVax also demonstrated reduction of glioma, pancreatic cancer, and breast cancer cell growth. No significant activation of complement or induction of autoantibodies was observed. The data provide mechanistic support for advancement of senolytic immunotherapy as a novel form of cancer therapy.

Link: https://doi.org/10.1186/s12967-025-07393-3