Time-restricted eating (TRE), a form of intermittent fasting that limits food intake within a consistent daily window, has gained attention as a feasible strategy to promote metabolic health and align eating with circadian rhythms. Aging and obesity share overlapping pathophysiological mechanisms, including increased visceral adipose tissue (VAT), chronic inflammation, and circadian disruption, which accelerate cardiometabolic decline and multimorbidity. In this Perspective, we examine TRE within a geroscience framework, integrating evidence from human trials and preclinical models to evaluate its potential relevance for aging-related processes. We discuss how the timing of food intake influences VAT distribution and glucose regulation, with early TRE schedules showing particular promise for enhancing nocturnal glycemic control and reducing abdominal subcutaneous adipose tissue. Drawing on circadian biology and caloric restriction literature, we highlight mechanistic insights linking feeding-fasting cycles to autophagy, nutrient sensing, and longevity. We also consider emerging evidence of sex-specific responses to TRE, which may inform personalized approaches. However, most clinical studies remain short-term and focus on cardiometabolic risk markers rather than validated measures of biological aging or functional outcomes. We therefore emphasize the need to distinguish between demonstrated metabolic benefits and proposed gerotherapeutic effects, and argue that future trials should incorporate biomarkers of biological age, circadian robustness, and physiological resilience. TRE represents a low-cost, scalable, and behaviorally simple intervention that could complement existing strategies in geromedicine to extend healthspan and delay age-related decline.

Cryobiology and geroscience share complementary goals in understanding and mitigating biological damage. Cryopreservation enables the long-term storage of living cells, tissues, and organs, with direct applications in aging-related interventions requiring transplantation, cell therapies, and regenerative approaches. Advances in cryopreservation technologies may expand biobanking of viable specimens across the lifespan, thus facilitating studies of aging phenotypes, biomarker discovery, drug screening, and therapeutic development. Notably, cryoinjury and biological aging share several common molecular features, including oxidative stress, DNA damage, protein misfolding, and mitochondrial dysfunction. These parallels suggest that repurposing geroscience-informed interventions may improve preservation outcomes by enhancing cellular resistance to cryogenic stress and post-thaw recovery. Here, representative opportunities at the interface of cryobiology and geroscience are summarized, emphasizing bidirectional strategies that may advance both fields. This Perspective builds upon discussions from the 2025 Quantitative Approaches and Understudied Questions in the Biology of Aging Workshop (Paris, France).

Aims: Increased gamma-aminobutyric acid type A (GABA_A) receptor activity has been identified in hypersomnolence syndromes, but its role and regional cerebral topography of receptor occupancy in excessive daytime sleepiness (EDS) in Parkinson’s disease (PD) is unknown. Dopaminergic functions or medications may contribute to EDS. Neuroimaging shows evidence of increased brain GABAergic activity in PD. We investigated the relationship between EDS, GABA_A receptor binding, striatal dopamine and dopaminergic medication use in PD.

Methods: Six PD patients underwent [¹¹C]flumazenil GABA_A receptor and [¹¹C]dihydrotetrabenazine (DTBZ) dopaminergic positron emission tomography (PET), clinical and Epworth Sleepiness Scale (ESS) assessments.

Results: Mean ESS score was 12.7 ± 4.5. Mean levodopa equivalent dose (LED) was 1,170 ± 616 mg. There was no significant correlation between nigrostriatal [¹¹C]DTBZ PET (R = 0.138, p = 0.792) or disease duration (R = 0.209, p = 0.902) and ESS scores. In contrast, there was a significant inverse relationship between striatal GABA_A receptor activity and ESS scores (β = -0.942, p = 0.024), more prominent in the caudate head (β = -0.949, p = 0.011). Therefore, frontal cortex binding was explored. A significant inverse relationship between frontal cortical GABA_A receptor activity and ESS (R = -0.884, p = 0.042) was found. A trend toward positive association between LED and ESS (R = 0.773, p = 0.053), was weakened (β = -0.128, p = 0.738) by the addition of caudate head GABA_A receptor activity into the model (β = -1.066, p = 0.055), suggesting that the association between LED and ESS may be mediated by GABAergic changes in the striatum.

Conclusion: Increased striatal and frontal cortical GABAergic activity is a more significant determinant of daytime somnolence than dopaminergic functions in PD. Findings may augur novel inverse GABA_A receptor agonist drug therapy for EDS in PD.

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.