How cellular senescence changes with age

What cellular senescence is, and how it changes with age

Cellular senescence is a stress response triggered by age-associated insults, defined operationally by irreversible cell-cycle arrest and accompanied by a pro-inflammatory secretory programme [1][4]. It is not a single molecular entity but a cell state, and it is therefore described by its markers and its secretory output rather than by a sequence, formula or molecular weight. The senescence-associated secretory phenotype (SASP) comprises inflammatory cytokines, chemokines, growth factors and matrix-remodelling enzymes that regulate the surrounding tissue microenvironment [4].

With age, senescent cells accumulate because clearance mechanisms become less effective; senescent cells are normally removed by the immune system but accumulate over time and are reported to contribute to metabolic dysfunction and impaired fitness [12]. Aging itself occurs heterogeneously across organs, producing progressive tissue dysfunction rather than a uniform decline [1].

The mechanistic work summarised here centres principally on DNA damage signalling through ATM and its upstream regulators, on the NF-κB arm of SASP induction, and on mitochondrial fission and biogenesis pathways in specific tissues [1][4][5][7].

Research Studies

LSD1 and ATM demethylation in DNA damage-mediated senescence and organ aging

Lysine-specific demethylase 1 (LSD1) was reported to be upregulated in aged organs and in senescent cells. In response to natural aging or ionizing radiation-induced DNA damage, LSD1 interacted with and demethylated ATM at lysine 3,016, confirmed using a newly generated ATM-K3016me antibody. This modification sustained ATM phosphorylation, amplified DNA damage signalling, and promoted senescence and organ aging [1].

SASP and remodelling of the tumour microenvironment

A review of the SASP literature describes its mechanisms of induction, its condition-dependent roles in cancer, its remodelling of the tumour microenvironment, and emerging strategies targeting senescent cells and SASP signalling [4]. The same review frames senescence as influencing cancer progression through irreversible cell-cycle arrest, immune surveillance and paracrine signalling [4].

Bone aging as multiscale degeneration

Bone aging is characterised in the reviewed literature not merely as bone mass loss but as a multi-level, networked degenerative phenomenon spanning molecular, cellular, tissue and system levels. At the macroscopic level it is described by declines in bone mass, microstructure and biomechanical properties [2].

ETS1/DRP1 and mitochondrial fission in intervertebral disc degeneration

In human nucleus pulposus cells (NPCs), ETS proto-oncogene 1 (ETS1) was identified as a regulator of mitochondrial fission. ETS1 was upregulated in severe human intervertebral disc degeneration and correlated with disc degeneration severity and NPC senescence. Inflammatory cytokines induced ETS1 upregulation, which directly bound to the dynamin 1-like (DNM1L, encoding DRP1) promoter; inhibition of the ETS1/DRP1 axis attenuated degeneration by suppressing excessive mitochondrial fission [7].

Nebivolol and TGF-β1-dependent endothelial senescence in hypertension

In a study of 71 patients with newly diagnosed hypertension randomly assigned to amlodipine, nebivolol or perindopril, serum collected before and 6 weeks after treatment was applied to endothelial cells in vitro to assess angiogenic activity, cellular senescence, mitochondrial metabolism and oxidative stress. Serum from patients with hypertension caused endothelial cell damage leading to senescence and a dysfunctional phenotype; nebivolol treatment was reported to improve hypertension-induced endothelial cell dysfunction by reducing TGF-β1-dependent senescence and normalising mitochondrial indices [8].

PQQ and mitochondrial function in skin aging models

Pyrroloquinoline quinone (PQQ) is a redox-active ortho-quinone that can participate in repeated redox cycling, protect mitochondrial function and activate signalling associated with mitochondrial biogenesis. A narrative review evaluates its mechanistic basis in intrinsic skin aging, photoaging, cellular senescence, impaired extracellular-matrix homeostasis, dysregulated pigmentation and recovery after energy-based or minimally invasive procedures, and notes major uncertainties [5].

Ergothioneine, OCTN1 and age-related disorders

Ergothioneine (EGT) is a diet-derived sulfur-containing histidine derivative with antioxidant, anti-inflammatory and cytoprotective properties. In humans its absorption, tissue distribution and long-term retention are mainly mediated by the organic cation transporter OCTN1, which may help explain its accumulation in metabolically active and stress-prone tissues. Experimental and clinical evidence links EGT to neurodegenerative, cardiovascular, metabolic, inflammatory and age-related disorders, although its therapeutic value still requires confirmation in larger and longer-term clinical studies [3].

Oxidative stress, SIRT1 and the gut microbiota in cognitive loss

A review addresses the neurocardiac basis of cognitive loss, noting that poor vascular perfusion can impair cognitive function in both Alzheimer's disease and multiple sclerosis, and that current treatments for cognitive impairment in cardiovascular disease, Alzheimer's disease, multiple sclerosis and diabetes often fail to fully address shared underlying cellular mechanisms [6].

Comparison of senescence models and reported interventions

Additional models reported in the literature

Senescence has also been examined as an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43^Q331K mice [9]; Hepassocin has been reported to prevent age-related liver senescence and facilitate liver regeneration by activating AMPK [10]; radiation-induced atrial fibrillation has been reported to be driven by cellular senescence via the GATA4–NF-κB pathway and rescued by D/Q senolytic therapy [11]; and blocking PD-L2 has been reported to prevent senescent cell accumulation and age-related dysfunction [12].

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Sources

• [1] LSD1-mediated demethylation of the DNA damage response factor ATM promotes senescence and organ aging. https://europepmc.org/article/PMC/PMC13574142
• [2] Bone aging: a paradigm of multiscale degeneration and targeted rejuvenation. https://europepmc.org/article/PMC/PMC13572547
• [3] Ergothioneine: Biosynthesis, Molecular Mechanisms, Physiological Function, and Role in Disease. https://europepmc.org/article/PMC/PMC13547098
• [4] A Review of Senescence-Associated Secretory Phenotype-Mediated Remodeling of the Tumor Microenvironment. https://europepmc.org/article/PMC/PMC13572038
• [5] Pyrroloquinoline Quinone (PQQ) as a Mitochondrial Rejuvenation Strategy in Aesthetic Dermatology. https://europepmc.org/article/PMC/PMC13510592
• [6] Oxidative stress, aging, metabolism, SIRT1, and the gut microbiota: the neurocardiac basis of cognitive loss. https://pubmed.ncbi.nlm.nih.gov/42545731/
• [7] Inhibition of ETS1/DRP1 axis attenuates intervertebral disc degeneration by suppressing excessive mitochondrial fission. https://pubmed.ncbi.nlm.nih.gov/42526698/
• [8] Nebivolol treatment improves hypertension-induced endothelial cell dysfunction by reducing TGF-β1-dependent senescence and normalizing mitochondrial indices. https://europepmc.org/article/PMC/PMC13566483
• [9] Cellular senescence is an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43^Q331K mice. https://pubmed.ncbi.nlm.nih.gov/42759848/
• [10] Hepassocin prevents age-related liver senescence and facilitates liver regeneration by activating AMPK. https://europepmc.org/article/PMC/PMC13575236
• [11] Radiation-induced atrial fibrillation is driven by cellular senescence via the GATA4 - NF-κB pathway and rescued by D/Q senolytic therapy. https://pubmed.ncbi.nlm.nih.gov/42743874/
• [12] Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction. https://pubmed.ncbi.nlm.nih.gov/42721966/