Aging & Longevity

Aging cells functionally decline and accumulate damage through poorly understood mechanisms. In this issue, Antentor et al. (https://doi.org/10.1083/jcb.202412064) find that increased vacuolar pH in older yeast cells slows clathrin-mediated endocytosis. These findings have broad implications in aging-related plasma membrane protein quality control.

Aging imposes a significant socioeconomic and healthcare burden worldwide, while effective therapy is still lacking. Impaired brain drainage and excessive accumulation of metabolites and toxins such as advanced glycation end products (AGEs) are characteristics of aging that contribute to the development of neurological disorders. Recent discoveries have highlighted the role of meningeal lymphatic vessels (MLVs) in the clearance of toxic metabolites, cells, tumors, and viruses from the brain,...

Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability in the elderly, characterized by the progressive destruction of cartilage, synovial inflammation, and subchondral bone remodeling. While mechanical stress, metabolic derangements, and systemic inflammation are recognized contributors, accumulating evidence underscores the pivotal role of impaired macroautophagy/autophagy in disease pathogenesis. Autophagy declines with age, depriving chondrocytes and...

Non-enzymatic reactions in glycolysis produce methylglyoxal (MGO), a reactive precursor to advanced glycation end-products (AGEs), which has been hypothesized to drive obesity, diabetes, and aging-associated pathologies. A combination of nicotinamide, α-lipoic acid, thiamine, pyridoxamine, and piperine (Gly-Low) lowers the deleterious effects of glycation by reducing MGO and the MGO-derived AGE, MG-H1, in mice. Gly-Low supplementation in the diet reduces food consumption, decreases body weight...

CONCLUSION: Evaluation of a person's IC at baseline explains additional variance compared to traditional frailty measures when predicting the risk of future negative health outcomes such as dementia incidence and mortality.

Chaperone-mediated autophagy (CMA) declines in ageing and neurodegenerative diseases. Loss of CMA in neurons leads to neurodegeneration and behavioural changes in mice but the role of CMA in neuronal physiology is largely unknown. Here we show that CMA deficiency causes neuronal hyperactivity, increased seizure susceptibility and disrupted calcium homeostasis. Pre-synaptic neurotransmitter release and NMDA receptor-mediated transmission were enhanced in CMA-deficient females, whereas males...

Age increases of brain amyloid plaques may be mediated by prior increase of soluble Aβ42. Here, we show that frontal cortex samples from brains of cognitively normal aging humans had progressively increased levels of soluble amyloid peptide Aβ40 throughout the lifespan. Aggregated amyloid fraction was subsequently obtained by formic acid, where Aβ42 showed increases only in humans over 90 years old when compared to those younger than 50. Similarly, aging wild-type mice without amyloid plaques...

Age and APOE ε4 are major risk factors for Alzheimer's disease (AD), while sex differences exist in disease prevalence and progression. Cerebrospinal fluid (CSF) proteomics can provide additional insights into brain aging and AD. To examine proteomic changes due to age, sex and apolipoprotein E (APOE) ε4 along with amyloid status before clinical AD occurs, we profiled 6,175 proteins in the CSF from 994 cognitively normal individuals aged 43-91 years. We identified and replicated 2,172...

Tissue-specific endothelial cells (ECs) regulate metabolism, inflammation, coagulation, organ development and regeneration. However, therapeutic application of EC transplantation requires scalable expansion of engraftable ECs that sustain their angiogenic and angiocrine functions. Here we identify a non-canonical aryl hydrocarbon receptor (AHR) pathway switched on by canonical AHR inhibitors that reactivates quiescent EC proliferation. Incubation of tissue-specific human ECs with AHR inhibitors,...

CONCLUSIONS: Our findings underscore the need for cross-national interventions that strengthen social support, increase opportunities for social participation, improve welfare provisions, and foster social integration to mitigate the cognitive health risks posed by social isolation, thereby promoting healthy aging globally.

CONCLUSIONS: This trial showed no significant improvements in cognitive and psychological outcomes after the PICMOA intervention. However, the findings raise important considerations regarding participants' familiarity with digital devices and intervention setting. Further research is needed to accumulate evidence on the duration and intensity of intervention and individual support for improving digital literacy.

Nicotinamide adenine dinucleotide (NAD^(+)) is an essential molecule involved in cellular metabolism, and its decline has been implicated in ageing and age-related disorders. However, evidence for an age-related decline in NAD^(+) levels in humans has been consistently observed only in a limited number of studies. Similarly, although preclinical studies support the idea that supplementation with NAD^(+) precursors is a promising therapeutic strategy to promote healthy ageing, human clinical...

CONCLUSION: Our findings suggest that a higher DDS was associated with a lower risk of disability in ADL among older Chinese adults. Greater efforts to promote a diverse diet should be targeted towards older adult for preventing disability in ADL.

Cellular senescence is a dynamic state in which cells permanently withdraw from the cell cycle while continuing to reshape their internal and external environment. It is characterized by persistent DNA damage responses, chromatin reorganization, and the secretion of a complex mixture of cytokines and proteases collectively known as the senescence-associated secretory phenotype (SASP). Transcriptomic and proteomic studies have defined key markers, including CDKN2A, CDKN1A, TP53, and SASP factors,...

Supplementation with ubiquinol 10 has been shown to improve the health of experimental animals and elderly individuals. The present study investigated the effects of lifetime supplementation with ubiquinol 10 on the progression of aging and lifespan in C57BL/6 mice, a standard strain for biomedical and aging research. A diet containing ubiquinol 10 (0.3 % w/w) and a control diet were fed to female C57BL/6J mice from 8 weeks of age until death, and the progression of senescence, lifespan, and...

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Mutations in the Lamin A (LMNA) gene, which encodes the Lamin A and C proteins, cause severe human diseases collectively known as laminopathies. These conditions are often devastating and lack effective therapies. In this study, we developed precise base editing (BE) strategies targeting the human LMNA gene variants L35P and R249Q, which cause congenital muscular dystrophy (CMD) and dilated cardiomyopathy with conduction defects (DCM-CD), respectively. Induced pluripotent stem cell-derived...

As Alzheimer's disease (AD) is diagnosed more frequently in women, understanding the role of sex has become a key priority in AD research. However, despite aging being the primary risk factor for AD, it remains unclear whether men and women differ in the extent of brain decline with age. Using 12,638 longitudinal brain MRIs from 4,726 participants aged 17 to 95 y across 14 cohorts, we examined sex differences in structural brain changes over time, controlling for differences in head size. Men...

Animals can typically maximize their fitness by reproducing throughout adulthood. Yet, in a handful of species, females cease reproduction long before death, highlighting an apparent evolutionary paradox. We used over three decades of life-history and behavioral data to examine the prevalence of postreproductive lifespan in wild mountain gorillas (Gorilla beringei beringei). Almost one third of females in our study population (7/25) have been "postreproductive" according to a commonly used...

Aging is a major risk factor for neurodegenerative diseases, yet the role of senescent microglia in age-related cognitive dysfunction remains incompletely understood. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been extensively studied for their significant potential in anti-aging. In this study, we demonstrated that hUC-MSCs ameliorate age-related cognitive decline and downregulate senescence-associated markers in the aged hippocampus. Furthermore, co-culture experiments...