Longevity Papers

Aging drives molecular changes that impair cellular and tissue function. Lipids are central to membrane structure, signaling and energy storage, yet their remodeling during aging remains unclear. Here, using cross-species, multi-tissue lipidomics, we identify elongation of lipid acyl chains as a conserved hallmark of aging across mice, Caenorhabditis elegans, Drosophila and humans. Similar lengthening occurs during the progression of human heart disease, whereas dietary restriction shortens cardiac lipids in mice. Integrated analyses reveal that aging is characterized by a shift toward longer lipids accompanied by depletion of shorter species, indicating ratiometric remodeling. Following this, we identify the lipid remodeler Plb1 as a regulator of this process, with expression correlating with lifespan in mice and genetic analyses supporting a causal role in human frailty. In C. elegans, Plb1 knockdown reverses lipid elongation and extends lifespan in a lipid-length-dependent manner. Together, these findings establish lipid chain length remodeling as a conserved, actionable hallmark of aging.

Autophagy dysfunction and senescence are established drivers of aging, but their potential interaction remains poorly understood. Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells. Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.

Population aging drives a parallel increase in muscle atrophy and cognitive decline, two major causes of disability in older adults. Mitochondrial dysfunction and chronic inflammation are core drivers of aging, with pyroptosis serving as a critical link between them. However, conventional single‑technique approaches capture only fragmented, static information and fail to bridge molecular events with whole‑organism phenotypes. This review introduces a unique integrative perspective that weaves established multimodal technologies ranging from molecular interaction analysis and absolute quantification to cellular metabolic and electrophysiological recordings, tissue clearing and laser microdissection, and finally to in vivo imaging and body composition analysis into a coherent, cross‑scale chain of evidence. By applying this paradigm to the mitochondria‑pyroptosis axis, we reveal how oxidative mitochondrial DNA enhances NLRP3 binding, how aged cells exhibit metabolic vulnerability and electrophysiological susceptibility, how pyroptotic hotspots form with spatial heterogeneity in tissues, and how pyroptosis signals quantitatively correlate with the decline in muscle mass and cognitive function. The core contribution of this review is the methodological framework of multimodal integration that enables causal tracing from molecular triggers to functional outcomes. This paradigm offers a transferable strategy for dissecting complex aging mechanisms and provides a theoretical foundation for targeting the mitochondria‑pyroptosis axis in precision anti‑aging interventions.

Cellular senescence, a key feature of ageing, involves irreversible cell cycle arrest and the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP) factors, which contribute to tissue degeneration and age-related diseases. Targeting senescent cells with senolytics, senomorphics and anti-ageing therapies marks a major shift in translational geroscience, with the potential to delay or reverse age-related conditions. A systematic review and narrative synthesis was conducted in accordance with PRISMA 2020 guidelines. Eligible human clinical studies evaluating pharmacological interventions targeting cellular senescence were included, comprising randomized and nonrandomized clinical trials and pilot studies reporting clinical, functional or senescence-associated outcomes. Data on study characteristics, interventions, efficacy, safety and senescence-associated biomarkers were extracted and synthesized qualitatively. Six completed clinical studies were included in the evidence synthesis, with one additional ongoing clinical trial identified separately. Senolytic interventions, particularly dasatinib plus quercetin, showed preliminary improvements in selected functional outcomes and reductions in senescence-associated biomarkers, while senomorphic and mTOR-targeting interventions demonstrated effects on selected tissue and immune-related outcomes. Reported adverse events were generally mild or manageable, but small sample sizes and short follow-up limited assessment of uncommon and long-term safety risks. Current evidence suggests that pharmacological targeting of cellular senescence is feasible and may produce measurable biological and functional effects in humans, but evidence remains insufficient to establish clinical efficacy or long-term safety. Senolytic and senomorphic strategies should therefore be considered investigational rather than established therapies. Larger, adequately powered randomized trials with standardized senescence biomarkers, clinically meaningful outcomes, longer follow-up and systematic safety assessment are needed.

Aging disrupts neural function, but whether impaired noradrenergic control of brain metabolism contributes to functional decline remains unclear. Using genetically encoded fluorescent sensors we measured metabolic and signaling responses in neurons and glia of living Drosophila brains following stimulation with octopamine, the invertebrate analogue of noradrenaline. Aging was accompanied by neurodegeneration, reduced locomotion and enhanced oxidative whole-brain metabolism. Octopamine increased D-glucose uptake selectively in astrocytes and elevated L-lactate in both astrocytes and neurons, consistent with astrocytic glycolysis coupled to neuronal L-lactate uptake; monocarboxylate transporter inhibition caused selective astrocytic L-lactate accumulation. In aged animals octopamine-evoked metabolic responses in astrocytes and neural Ca2+ transients were markedly reduced. This impairment was associated with lower expression of adrenoceptor-like tyramine 1 receptor (Tyr1R). Selective Tyr1R overexpression in (nor)adrenergic-like Tdc2 neurons prolonged lifespan, restored Ca2+ signalling and improved locomotor performance. These findings identify Tyr1R-dependent Ca2+ signalling as an age-sensitive regulator of brain metabolism and motor function.

DE-SWAN is a commonly used method to study how large ensembles of omics biomarkers change across the life course. It has been used to demonstrate apparent repeated accelerations and decelerations of aging rates across the life course, including 2-3 peaks of aging-related changes. This result contradicts what is expected based on the demography of aging and known biological mechanisms. Here, we use simulations to study the robustness of DE-SWAN to the age distribution of the study sample and to choice of window size. We show that under many realistic scenarios, DE-SWAN is highly sensitive to factors unrelated to the underlying rates of change in aging biology. This calls into question the results of previous analyses that have attributed DE-SWAN peaks to acceleration and deceleration of aging. We conclude that the method is unreliable for studying rates of change across the life course under most circumstances.