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28 April 2026 - 03:41 PM
Targeting Senescent Cells as a Treatment for Chronic Obstructive Pulmonary Disease 28 April 2026 - 10:22 AM
Presently largely irreversible lung disease like idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease were one of the first conditions targeted for the development of senolytic therapies to clear senescent cells. A range of evidence supports a prominent role for an increased burden of senescent cells in airway and lung tissues in these conditions. Here, researchers discuss a more recent approach to senolytic therapy, employing a proteolysis-targeting chimera approach to make the cell break down one of the proteins involved in senescent cell survival. Senescent cells, unlike normal cells, are primed to undergo the programmed cell death of apoptosis. They are only held back from that fate by the activity of a few proteins, including BCLXL, which is the target here. When levels of BCLXL are dramatically reduced, senescent cells undergo apoptosis while normal cells are largely unaffected.
Ageing and cellular senescence significantly contribute to the progression of age-related diseases, particularly chronic obstructive pulmonary disease (COPD). Cellular senescence refers to the cessation of cell division in response to stress and damage. While senescent cells remain metabolically active, they secrete pro-inflammatory factors that drive disease progression. Senolytic therapies aim to selectively target and eliminate these senescent cells by inducing their apoptosis. This study examines the senolytic potential of BCLXL-PROTAC, a novel proteolysis-targeting chimera designed to degrade BCLXL, in small airway epithelial cells and fibroblasts from patients with COPD.
Treatment of COPD small airway epithelial cells and fibroblasts with BCLXL-PROTAC led to their apoptosis through the activation of caspase 3, along with a reduction in senescence markers such as p21CIP1, p16INK4a, and senescence-associated β-galactosidase. The effects of BCLXL-PROTAC were selective for senescent cells and did not affect non-COPD cells. The clearance of COPD small airway epithelial cells and fibroblasts by BCLXL-PROTAC was associated with an increase in the proliferation marker Ki67 and enhanced cell proliferation. Additionally, in precision-cut lung slices obtained from COPD patients, BCLXL-PROTAC significantly reduced p21CIP1 expression in the airway epithelium, validating its effectiveness in a more complex tissue environment.
These findings demonstrate that BCLXL-PROTAC is a potent and selective senolytic agent that may promote lung cell rejuvenation, supporting its potential as a novel therapeutic strategy for age-related diseases, including COPD.
Link: https://doi.org/10.1111/acel.70487
View the full article at FightAging
Senescent Macrophages are Important in Liver Aging and Liver Disease 28 April 2026 - 10:11 AM
Senescent cells accumulate with age, but not all senescent populations are equal. Evidence suggests that some types of senescent cell cause more harm than others, and the research here is an example of this. Researchers find that a population of senescent macrophages in liver tissue acts as an important driver of chronic inflammation and dysfunction in liver aging and the metabolic liver disease associated with excess fat tissue that leads to cirrhosis and cancer. Senolytic therapies that selectively destroy the senescent macrophages reduce liver inflammation and liver dysfunction in mice, proving the point.
Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21+Trem2+ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling.
We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.
Link: https://doi.org/10.1038/s43587-026-01101-6
View the full article at FightAging
Does Exposure to Air Pollution Literally Accelerate Aging? 27 April 2026 - 06:22 PM
It is well established that long term exposure to forms of air pollution increases the risk of mortality and numerous age-related conditions. The mechanisms of interest revolve around increased systemic chronic inflammation that is provoked by the interaction of pollutants, such as fine particles, with airway and lung cells. Is this exposure and its consequences a form of accelerated aging? The question of whether one environmental factor or another accelerates aging forces us to consider how aging is defined and measured. Hitting people with hammers repeatedly will certainly increase mortality, and may even increase common measures of biological age, such as epigenetic clocks, but is it producing accelerated aging? One can debate the question, but clearly more biological data would be needed to actually answer it. Looking only at mortality or loss of function is insufficient, one has to also think about what is going on under the hood in the biochemistry of cells.
In today's open access paper, researchers correlate forms of air pollution, several different measures of biological age, and dementia risk. The greater the exposure to air pollution, the greater the increase in biological age measures and the greater the risk of dementia. Under the hood, there is more inflammation, a greater burden of senescent cells, and likely other features of aging to a greater degree. Biological age measures such as epigenetic clocks tend to obscure all of that, however. Senescent cell burden is perhaps a helpful way to think about the effects of exposure and whether those effects are in fact accelerating aging. Senescent cells accumulate with age, and the more there are the worse the outcome. They are a form of damage that negatively impacts tissue structure and function over time. We might consider any exposure that robustly increases senescent cell burden to be creating accelerated aging; consider obesity, for example, or chemotherapy. There are numerous other forms of aging-associated cell and tissue damage that we can measure, and to the degree that they are increased, we can suggest that this increase reflects an increased biological age.
Air pollution is globally ubiquitous and has been identified as a risk factor for global disease burden. Limited epidemiological studies have linked air pollution to morphological brain alterations, with inconsistent findings, and most of them have focused only on a single type of regional brain region. Furthermore, although air pollution has been established as a risk factor for dementia, the underlying neurobiological mechanisms are poorly understood. Recent evidence suggests that air pollution may accelerate systemic biological aging.
Given that dementia is fundamentally an age-related neurodegenerative disorder, accelerated biological aging is a plausible, upstream mediator in the pathway from air pollution exposure to dementia. Since individuals age at different rates, quantifying biological aging rather than chronological age may reveal a more precise mechanistic link between exposure and health outcomes. Together, we propose a novel mechanistic hypothesis: exposure to air pollution may first accelerate systemic biological aging, which in turn drives the degeneration of specific brain structures, ultimately leading to the onset of dementia.
Therefore, using data from the UK Biobank, we aimed to: (1) examine the associations of long-term exposure to five air pollutants (PM2.5, PM10, PM2.5 absorbance, NO2, and NOx) with global gray/white matter volumes, 80 regional gray matter volumes, and incident dementia; (2) assess the association between biological age acceleration and both air pollution and incident dementia; and (3) investigate the mediating roles of biological aging acceleration and brain structure alterations underlying the air pollution-dementia association.
Cox proportional hazards regression models were used to evaluate the association between air pollution and incident dementia, while linear regression models were used to assess its associations with global and 80 regional brain structures. The mediating roles of biological aging acceleration (measured by Klemera-Doubal method Biological Age [KDM-BA] and PhenoAge) and brain structures in the air pollution-dementia association were evaluated using structural equation modeling (SEM).
Compared to participants with the lowest tertile of air pollution exposure, those in the highest exposure group had higher risks of dementia (Hazard ratio, HR: 1.141 for PM2.5; 1.09 for PM10; 1.09 for PM2.5 absorbance; 1.20 for NO2; and 1.14 for NOX). Air pollution exposure was inversely associated with global and several regional brain structural alterations. SEM revealed a consistent mediating pathway that integrates biological aging and brain structural alterations in the association between air pollution exposure and the risk of dementia.
View the full article at FightAging
A Robust Senescence Response Helps Wounds Heal 27 April 2026 - 04:20 PM
A team of scientists has examined how younger and older mice heal from wounds and found that more robust senescent cell activation in younger animals helps them heal faster.
A double-edged sword
Multiple experiments have found that senescent cells and proper wound healing are intrinsically linked. Zebrafish are well-known to completely regenerate tissue, but an experiment found that the blanket removal of senescent cells impairs this ability [1]. Removing senescent cells from 2-month-old mice impaired their wound healing as well [2].
However, it is well-known that older people heal slower from wounds while having more cellular senescence throughout the body. These researchers decided to take a closer look at this phenomenon at the cellular level.
When young people have more senescent cells
In the first experiment, the researchers cut one-centimeter wounds through the back fat of 2-month-old and 24-month-old mice, which were given painkillers and kept from infection. Unsurprisingly, the wounds of the older mice healed much slower than those of the younger mice; by week 18, the wounds of the younger mice had fully closed, while it took the older mice 24 days to heal.
This was linked to the transient activation of senescent cells. Before the wound, the aged mice had more senescent cells in the area than the younger mice did, as measured by the two well-known biomarkers p16 and SA-β-gal; a week after wounding, however, only the younger mice exhibited sharp upregulations of both of these biomarkers, and this was confirmed by an examination of p16 mRNA gene expression. Another senescence-associated biomarker, p21, was upregulated only in the young mice two weeks after wounding, which was also confirmed by an mRNA analysis.
The SASP had similar temporary changes. In the younger mice, the increase in senescent cells within a week was matched by transient increases in well-known inflammatory factors, including tumor necrosis factor (TNF) and IL-6, along with factors that remodel the extracellular matrix. In the aged mice, however, the increase in IL-6 was prolonged compared to the young mice, the matrix-remodeling factor MMP8 was also elevated for longer, and many of the other factors were not significantly elevated at all.
Going senescent for a reason
Looking closely at the cells at the wound site, the researchers isolated a “defined senescent” population. These were cells that had upregulated p16 and p21 levels and did not express the proliferation marker Mki67. Most of these cells were fibroblasts, although other immune and tissue cells were present in this population as well. The authors described the fibroblasts as having a ‘transcriptionally active program’ that led to upregulated SASP factors.
Rather than inflammation, most of these upregulated factors were related to matrix regulation and growth, which clearly play significant roles in wound healing. These findings were corrobrated with human data: a public dataset of RNA sequencing data derived from younger people’s wounds found similar upregulations in ECM remodeling and deposition.
Unsurprisingly, these upregulated factors were less present in older animals. The older mice had a less robust response at the cellular level; their senescent cells were less heterogenous. Unlike the younger mice, they were more prone to expressing inflammatory factors as part of the SASP, and there was less activation of matrix-deposition factors. The older cells’ signaling, according to the authors, suggests “a dysfunctional, stressed state rather than a reparative one”.
In sum, young senescent wound fibroblasts mount a prorepair chemokine and ECM-remodeling program and broadcast it to their neighbors, whereas aged senescent wound fibroblasts lose that reparative signaling and instead exhibit proteotoxic/inflammatory features that fail to promote efficient healing.
Just as there is a difference between acute inflammation and the chronic inflammation known as inflammaging, this study’s results show a clear difference between transient and permanent senescence. A “senescent cell” is simply one that no longer divides, and there is obviously a distinction between cells that become activated to become senescent to perform a specific task and cells that have been gradually driven senescent through aging. Promoting the former while eliminating the latter is a difficult but necessary job in dealing with this aspect of aging.
Literature
[1] Da Silva‐Álvarez, S., Guerra‐Varela, J., Sobrido‐Cameán, D., Quelle, A., Barreiro‐Iglesias, A., Sánchez, L., & Collado, M. (2020). Cell senescence contributes to tissue regeneration in zebrafish. Aging cell, 19(1), e13052.
[2] Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., … & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733.
View the article at lifespan.io
