Replicative senescence links telomere shortening to irreversible proliferative arrest and is widely recognized as a major tumor-suppressive mechanism. At the organismal level, however, progressive accumulation of senescent cells contributes to tissue dysfunction, chronic inflammation, and aging. Accumulating evidence suggests that telomere shortening influences telomeric and subtelomeric chromatin organization and transcription through mechanisms that remain incompletely understood. Building upon the telomere position effect model of cellular senescence and the subtelomere-telomere theory of aging, this review proposes a chromatin-sensing telomere theory of aging in which telomere shortening contributes to senescence through epigenetic and transcriptional changes at chromosome ends. Central to this model is TERRA, a long non-coding RNA that regulates telomeric chromatin structure, telomere maintenance, and DNA-damage responses. The lysine methyltransferase MLL/KMT2A is a key regulator of TERRA transcription. MLL associates with telomeric chromatin in a telomere length-dependent manner and promotes TERRA transcription through H3K4 methylation. Shelterin components, particularly TRF2, can repress TERRA transcription in certain experimental contexts, and we propose that telomere shortening progressively remodels the shelterin-dependent telomere-subtelomere chromatin environment, potentially reducing access of MLL and RNA polymerase II to subtelomeric promoters. A biphasic model of TERRA regulation is proposed in which early TERRA upregulation in aging tissues promotes telomere protection, while subsequent critical shortening of TERRA-dominant telomeres contributes to reduced TERRA expression, telomere dysfunction, and senescence. This theory proposes a mechanistic link between telomere shortening, chromatin regulation, and quasi-programmed aging.
Vascular endothelial cell (VEC) senescence is a key contributor to vascular aging and atherosclerosis. Increasing evidence suggests that long non-coding RNAs (lncRNAs) can encode functional micropeptides involved in cellular regulation. In this study, we investigated whether 17β-estradiol (17β-E2) delays endothelial senescence through an lncRNA-encoded peptide associated with autophagy. RNA sequencing was performed in H2O2-induced senescent human umbilical vein endothelial cells (HUVECs) treated with or without 17β-E2, and differentially expressed lncRNAs with coding potential were identified through GO/KEGG analyses and bioinformatics prediction. LncRNA SEPT5-GP1BB was found to encode a 453-amino-acid peptide termed ARP, whose expression was reduced during endothelial senescence but restored by 17β-E2 treatment. Functional experiments demonstrated that 17β-E2 promoted autophagy through ARP rather than through the lncRNA transcript itself. ARP overexpression increased LC3B expression, reduced p62 accumulation, decreased senescence-associated β-galactosidase activity, suppressed SASP-related gene expression, and alleviated oxidative stress in senescent HUVECs. Furthermore, these protective effects were largely abolished by chloroquine treatment, indicating that autophagy mediated the anti-senescent effects of ARP. Collectively, these findings demonstrate that 17β-E2 delays endothelial senescence by upregulating the lncRNA SEPT5-GP1BB-encoded peptide ARP, which promotes autophagy, suggesting that ARP may serve as a potential therapeutic target for vascular aging.
Aging is accompanied by alterations in inflammatory signaling, regulated cell-death pathways, and cellular stress responses in the brain. This study investigated the effects of propolis and dexpanthenol, administered individually or in combination, on gasdermin-related, inflammatory, and heat-shock gene expression in naturally aged male mice. Thirty-five male CD-1 mice were randomly allocated to five groups (n = 7/group): Young Control, Aged Control, Aged + Propolis, Aged + Dexpanthenol, and Aged + Propolis + Dexpanthenol. Propolis (200 mg/kg/day) and dexpanthenol (500 mg/kg/day) were administered for 14 days. Whole-brain mRNA expression of GSDMD, GSDME, GSDMC, TNF-α, IL-1β, HSP70, and HSP90 was evaluated by quantitative real-time PCR. Natural aging was associated with marked reductions in TNF-α, IL-1β, and HSP70 expression, whereas GSDMD, GSDME, GSDMC, and HSP90 were not significantly altered after correction for multiple comparisons. Propolis reduced GSDME and IL-1β expression while increasing GSDMC relative to aged controls. Dexpanthenol increased GSDMD and HSP70 expression, shifted TNF-α toward the young-control profile, and reduced HSP90 expression. Combined administration produced a distinct transcriptional profile characterized by pronounced increases in GSDMD, TNF-α, IL-1β, and HSP70 relative to aged controls. These findings indicate that propolis and dexpanthenol are associated with distinct, gene-specific transcriptional responses in the naturally aged brain rather than uniform changes across the inflammatory and gasdermin-related genes examined. Because the analyses were restricted to mRNA expression, the observed gasdermin transcriptional changes do not establish functional pyroptosis. The prominent HSP70 response further suggests that cellular stress adaptation and proteostasis may represent important components of these treatment-associated molecular changes.
The Mexican cavefish, Astyanax mexicanus, is a powerful evolutionary model for investigating how adaptation to extreme environments reshapes vertebrate physiology. Multiple cave populations have independently evolved under subterranean conditions, acquiring traits including insulin resistance, persistent hyperglycaemia, increased adiposity, altered sleep patterns, hypoxia tolerance and extensive metabolic reprogramming. Despite these differences, cavefish exhibit lifespans comparable to those of surface fish, while selected traits, including fertility and locomotor performance, appear to be better preserved with age. These observations challenge the assumption that persistent metabolic dysfunction necessarily entails accelerated functional decline and raise the possibility that cavefish have evolved mechanisms of ageing resilience. This narrative review examines evidence linking cave adaptation to biological processes relevant to ageing, focusing on nutrient sensing, lipid metabolism, mitochondrial function, redox homeostasis and immune regulation. Rather than eliminating metabolic stress, cave-associated adaptations may buffer some of its downstream consequences, preserving selected physiological functions. Evidence is evaluated within the framework of the hallmarks of ageing, considering genomic instability, telomere dynamics, deregulated nutrient sensing, mitochondrial dysfunction and chronic inflammation, while identifying major knowledge gaps regarding epigenetic alterations, loss of proteostasis, macroautophagy, cellular senescence, stem-cell exhaustion, altered intercellular communication and dysbiosis. The available evidence supports A. mexicanus as a comparative model for investigating how chronic environmental and metabolic stress can be uncoupled from selected aspects of functional decline. Distinguishing delayed ageing from enhanced tolerance or compensation in response to accumulated damage will be essential to establish the extent and mechanisms of ageing resilience in this species.
Biological age estimation is increasingly used in aging research, but evaluation often relies too heavily on mean absolute error (MAE) against chronological age. We conducted a narrative review of major molecular aging clocks and propose an operational framework that links clock selection to the intended task. Applications are organized into four tasks: chronological-age estimation, age-independent deviation, future disease or mortality risk, and longitudinal monitoring of aging pace or intervention response. For each task, the framework specifies the target construct, output, preprocessing and confounding checks, validation metrics, and interpretation limits. A complementary four-layer model distinguishes relatively stable molecular measures, pace-of-aging measures, dynamic functional markers, and organ-specific vulnerability. Published examples illustrate why no single metric is sufficient: low age-prediction error does not establish clinical relevance, and strong risk association does not establish responsiveness to intervention. Aging clocks should therefore be evaluated as task-bound measurement tools, with explicit attention to calibration, discrimination, reliability, transportability, uncertainty, and incremental value. This framework is intended to support transparent model selection, reporting, and interpretation rather than designate a universally superior clock.
