Cells rely on lysosomes and autophagy to maintain homeostasis under fluctuating environmental and metabolic conditions. However, how these degradative systems are dynamically coordinated across stress, senescence, and aging remains incompletely understood. Transcription factor EB (TFEB), a member of the microphthalmia/transcription factor E (MiT/TFE) family, has emerged as a key regulator of lysosomal biogenesis and autophagy by controlling the coordinated lysosomal expression and regulation (CLEAR) gene network, integrating nutrient sensing, mitochondrial status, Ca²⁺, redox signaling, and mechanistic target of rapamycin complex 1 (mTORC1) activity. While TFEB activation promotes lysosomal and metabolic adaptation during acute stress, accumulating evidence indicates that its activity is tightly constrained in time and magnitude, and that altered TFEB dynamics critically shape cellular fate decisions. Here, we synthesize current findings showing that transient TFEB activation supports stress resilience and recovery. In contrast, persistent, insufficient, or dysregulated TFEB signaling contributes to divergent senescence trajectories and age-associated decline in proteostasis. We further discuss how defects in TFEB regulation underlie impaired autophagy–lysosome function during aging across tissues. Notably, both insufficient and excessive TFEB activity can be maladaptive. Together, this framework positions TFEB as a dynamically regulated node linking stress adaptation, senescence progression, and aging, and highlights the need for context- and tissue-specific strategies aimed at restoring TFEB responsiveness rather than constitutively enhancing its activity.

Aims: Testing the hypothesis that excess mutations induced in primary fibroblasts by a low dose of N-ethyl-N-nitrosourea (ENU) are inversely correlated with species-specific maximum life span.

Aims: Testing the hypothesis that excess mutations induced in primary fibroblasts by a low dose of N-ethyl-N-nitrosourea (ENU) are inversely correlated with species-specific maximum life span.

Methods: To measure excess mutations induced by ENU we treated primary cells of 10 mammalian species, greatly differing in life span. We treated all cells with a low dose, non-toxic dose of ENU (20 ug/ml). We then extracted DNA from all treated and untreated cells and quantified somatic mutation burden by single-molecule sequencing. We measured excessive mutations by calculating the ΔSNVs and we analyzed this across species with linear regression.

Results: The average values for ΔSNV were found to range from 0.773 in mice to 0.367 in whale, resulting in a modest inverse correlation with species-specific maximum life span (R² = 0.2067, P < 0.001).

Conclusion: We conclude that DNA repair accuracy, the main determinant of genome sequence integrity, modestly correlates with life span suggesting that longer lived species have better repair capacities compared to shorter-lived species, which is in keeping with genome instability being a primary hallmark of aging and highlights its important role for longevity.

Autophagy is a conserved cellular clearance pathway that supports homeostasis by removing damaged or superfluous intracellular components. Within microglia, autophagy is emerging as a regulator of key processes that modify neurodegeneration, including phagocytosis, cytokine secretion, and senescence. Many studies that have examined the effect of disrupted autophagy on microglial functions have used genetic knockouts of the machinery required to conjugate microtubule-associated light chain 3 (LC3) to the autophagic membrane. However, much of this molecular machinery is also required for a set of distinct but related pathways known as the conjugation of ATG8s to single membranes (CASM). CASM includes processes of particular importance in microglia, such as LC3-associated phagocytosis and LC3-associated endocytosis. It is thus not clear which of the effects of the disruption of LC3 conjugation in microglia are attributable to the loss of autophagy or the loss of CASM function. In this review, we describe the mechanisms of autophagy and CASM and highlight the effects of the loss of these pathways on key microglial processes relevant to brain ageing and neurodegenerative diseases. We discuss recent literature that has revealed the effects of ageing and neurodegeneration on microglial autophagy, and the effects of microglial autophagy and/or CASM disruption on key microglial functions such as phagocytosis, cytokine secretion, and senescence. Finally, we discuss the potential therapeutic implications of these findings for neurodegeneration and highlight key unanswered questions for future research.

Accumulating evidence has indicated that the normal tissue adjacent to tumor (NAT) is distinct from both healthy and tumor tissues. It is suggested that the crosstalk between NAT and tumor tissues helps shape the tumor microenvironment and promotes cancer progression, but the molecular and cellular evidence for this crosstalk is scarce. In this perspective, we propose that NAT tissue constitutes a unique “peritumoral microenvironment (Peri-TME)” mostly conditioned by the tumor. Furthermore, cellular senescence is identified as a key characteristic of Peri-TME, which accelerates tumor growth, as illustrated in our recent studies in colorectal cancer (CRC). Finally, strategies to target the senescent Peri-TME may represent an effective means to disrupt the vicious interaction between Peri-TME and Tumor and enhance therapeutic efficacy.

Aging is a heterogeneous, multi-system process driven by the interplay between accumulating molecular damage and the progressive erosion of resilience. While damage accumulates in a ubiquitous and homogeneous fashion, resilience is finite and unequally distributed across physiological systems and individuals, yielding distinct biological trajectories that diverge early in life, giving rise to the individual-specific decline in physiological function and the manifestation of a diverse spectrum of organ-specific diseases, and converge only when multisystem dysregulation overwhelms compensatory capacity. Early deviations in mitochondrial function, proteostasis, inflammation, and metabolic regulation often remain clinically silent, detectable only through gerodiagnostics, longitudinal, sensitive biomarkers of aging. Yet most biomarkers were developed to detect disease rather than quantify aging biology, and their mechanistic specificity declines with advancing multimorbidity. Precision geromedicine therefore requires the integration of gerodiagnostics that capture system-level resilience and stress responsiveness with measures of functional reserve, behavior, physiology, and the exposome, enabling the identification of individualized aging trajectories and the biological pathways that drive them. This combined approach clarifies causal pathways, enables earlier detection of vulnerability and supports individualized gerointerventions that modify aging trajectories rather than specifically but narrowly focusing on individual age-related diseases.