Longevity Papers

Obesity, a global epidemic linked to around 4 million deaths yearly, arises from lifestyle imbalances impacting inflammation-related conditions like non-alcoholic fatty liver disease and gut dysbiosis. But the long-term effects of inflammation caused by lifestyle-related dietary changes remain unexplained. In this study, we used young male C57Bl/6 mice which were fed either an obesogenic diet (OBD) or a control diet (CON) for six months. Later, a group of mice from the OBD group were intervened to the CON diet (OBD-R) for four months, while another OBD group remained on the OBD diet. The OBD induced distinct changes in gut microbial, notably elevating Firmicutes and Actinobacteria, while reducing Bacteroidetes and Tenericutes. OBD-R restored microbial abundance like CON. Analyzing liver, plasma, and fecal samples revealed OBD-induced alterations in various structural and bioactive lipids, which were normalized to CON in the OBD-R, showcasing lipid metabolism flexibility and adaptability to dietary shifts. OBD increased omega 6 fatty acid, Arachidonic Acid (AA) and decreased omega 3-derived lipid mediators in the OBD mimicking non-alcoholic fatty liver disease thus impacting inflammation-resolution pathways. OBD also induced hepatic inflammation via increasing alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and proinflammatory markers CCR2, TNF-α, and IL-1β in liver. Transitioning from OBD to CON mitigated inflammatory gene expression and restored lipid and cholesterol networks. This study underscores the intricate interplay between lifestyle-driven dietary changes, gut microbiota, lipid metabolism, and liver health. Notably, it suggests that shift from an OBD (omega-6 enriched) to CON partially alleviates signs of chronic inflammation during aging. Understanding these microbial, lipidomic, and hepatic inflammatory dynamics reveals potential therapeutic avenues for metabolic disorders induced by diet, emphasizing the pivotal role of diet in sustaining metabolic health.

In aging populations, understanding predictors of cognitive decline is essential. We aimed to investigate the risk of cognitive decline and dementia by sensory impairments across sex, age, and European regions, and examined the mediating role of activities of daily living (ADL), physical activity, and depressive symptoms.

Declines in lysosomal acidification and function with aging are observed in organisms ranging from yeast to humans. V-ATPases play a central role in organelle acidification and V- ATPase activity is regulated by reversible disassembly in many different settings. Using the yeast

Cardiovascular disease (CVD) remains a leading cause of mortality and morbidity globally, particularly among older adults. In India, the rapid demographic transition has resulted in a significant increase in the aging population, necessitating a deeper understanding of the factors influencing CVD prevalence. This study examines the association between physical activity and the prevalence of CVD among individuals aged 60 and above.

This study compared the mortality risk of long-lived siblings with the U.S. population average and their spouse controls, and investigated the leading causes of death and the familial effect in death pattern.

To diminish the negative influence of sarcopenia on senior adults, the study aimed to investigate the association between adherence to 24-h movement behavior guidelines (physical activity, sedentary behavior, sleep duration) and the risk of sarcopenia among individuals aged ≥55 years in five low- and middle-income countries (LMICs).

Resistance exercise provides significant benefits to skeletal muscle, including hypertrophy and metabolic enhancements, supporting overall health and disease management. However, skeletal muscle responsiveness to resistance exercise is significantly reduced in conditions such as aging and diabetes. Recent reports suggest that glycation stress contributes to muscle atrophy and impaired exercise-induced muscle adaptation; however, its role in the muscle response to resistance exercise remains unclear. Therefore, in this study, we investigated whether methylglyoxal (MGO), a key factor in glycation stress, affects the acute responsiveness of skeletal muscles to resistance exercise, focusing on protein synthesis and the key signaling molecules. This study included 12 8-week-old male Sprague-Dawley rats divided into two groups: one received 0.5% MGO-supplemented drinking water (MGO group) and the other received regular water (control group). After 10 weeks, the left tibialis anterior muscle of each rat was subjected to electrical stimulation (ES) to mimic resistance exercise, with the right muscle serving as a non-stimulated control. Muscle protein-synthesis rates were evaluated with SUnSET, and phosphorylation levels of key signaling molecules (p70S6K and S6rp) were quantified using western blotting. In the control group, stimulated muscles exhibited significantly increased muscle protein synthesis and phosphorylation levels of p70S6K and S6rp. In the MGO group, these increases were attenuated, indicating that MGO treatment suppresses the adaptive response to resistance exercise. MGO diminishes the skeletal muscle's adaptive response to ES-simulated resistance exercise, affecting both muscle protein synthesis and key signaling molecules. The potential influence of glycation stress on the effectiveness of resistance exercise or ES emphasizes the need for individualized interventions in conditions of elevated glycation stress, such as diabetes and aging.

The challenges posed by an aging society are increasingly recognized, particularly regarding the potential impacts of high-fat diets and the trend toward younger ages of disease onset. The purpose of this study was to clarify the relationships between the prevalence of stroke in the general US population and PhenoAge (PA) and PhenoAgeAccel (PAA).

Germline regulates the expression of life-history traits and mediates the trade-off between reproduction and somatic maintenance. However, germline maintenance in itself can be costly, and the costs can vary between the sexes depending on the number of gametes produced across the lifetime. We tested this directly by germline ablation using glp-1 RNA interference (RNAi) in a dioecious nematode Caenorhabditis remanei. Germline removal strongly increased heat-shock resistance in both sexes, thus confirming the role of the germline in regulating somatic maintenance. However, germline removal resulted in increased lifespan only in males. High costs of mating strongly reduced lifespan in both sexes and obliterated the survival benefit of germline-less males even though neither sex produced any offspring. Furthermore, germline removal reduced male growth before maturation but not in adulthood, while female growth rate was reduced both before and especially after maturation. Thus, germline removal improves male lifespan without major growth costs, while germline-less females grow slower and do not live longer than reproductively functional counterparts in the absence of environmental stress. Overall, these results suggest that germline maintenance is costlier for males than for females in C. remanei.

Adipose tissue is a large endocrine organ that serves numerous physiological functions. As we age, adipose tissue remodels and can develop functional changes that alters its phenotype, potentially contributing to metabolic and cardiovascular disorders. Aging adipose tissue is characterized by regional redistribution of fat, accumulation of senescent cells, fibrosis, and decline in adipocyte differentiation capacities, which collectively impact adipose tissue function and whole body health. A notable transformation involves increased accumulation of intra-abdominal visceral adipose tissue and ectopic fat around internal organs such as the heart, blood vessels, liver, and kidneys that alter their functions. Other changes associated with aging include alterations in adipokine secretion and changes in adipocyte size and numbers. Aging adipocytes play a role in mediating chronic inflammation, metabolic dysfunction, and insulin resistance. Visceral adipose tissue, which increases in volume with aging, is in particular associated with inflammation, angiogenic dysfunction, and microvascular abnormalities, and mediators released by visceral fat may have adverse consequences systemically in multiple target organs, including the cardiovascular system. Understanding mechanisms underlying adipose tissue aging and its impact on cardiovascular health are important for developing interventions and treatments to promote healthy aging and reduce cardiometabolic disease risk.

JOURNAL/nrgr/04.03/01300535-202505000-00026/figure1/v/2024-07-28T173839Z/r/image-tiff Loss of synapse and functional connectivity in brain circuits is associated with aging and neurodegeneration, however, few molecular mechanisms are known to intrinsically promote synaptogenesis or enhance synapse function. We have previously shown that MET receptor tyrosine kinase in the developing cortical circuits promotes dendritic growth and dendritic spine morphogenesis. To investigate whether enhancing MET in adult cortex has synapse regenerating potential, we created a knockin mouse line, in which the human MET gene expression and signaling can be turned on in adult (10-12 months) cortical neurons through doxycycline-containing chow. We found that similar to the developing brain, turning on MET signaling in the adult cortex activates small GTPases and increases spine density in prefrontal projection neurons. These findings are further corroborated by increased synaptic activity and transient generation of immature silent synapses. Prolonged MET signaling resulted in an increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-D-aspartate (AMPA/NMDA) receptor current ratio, indicative of enhanced synaptic function and connectivity. Our data reveal that enhancing MET signaling could be an interventional approach to promote synaptogenesis and preserve functional connectivity in the adult brain. These findings may have implications for regenerative therapy in aging and neurodegeneration conditions.

Physical activity is associated with lower risk of dementia and cognitive impairment, but existing randomized controlled trials have shown conflicting results. As cognitive decline occurs decades before the onset of dementia, physical activity interventions initiated in late life may have missed the potential window for prevention. An ideal trial of physical activity initiated from midlife and lasts till incident dementia and cognitive impairment in late life is not feasible. We aimed to estimate the effectiveness of a hypothetical physical activity intervention initiated from midlife on reducing dementia and cognitive impairment by emulating target trials using observational data.

Epigenetic aging clocks have been widely used to validate rejuvenation effects during cellular reprogramming. However, these predictions are unverifiable because the true biological age of reprogrammed cells remains unknown. We present an analytical framework to consider rejuvenation predictions from the uncertainty perspective. Our analysis reveals that the DNA methylation profiles across reprogramming are poorly represented in the aging data used to train clock models, thus introducing high epistemic uncertainty in age estimations. Moreover, predictions of different published clocks are inconsistent, with some even suggesting zero or negative rejuvenation. While not questioning the possibility of age reversal, we show that the high clock uncertainty challenges the reliability of rejuvenation effects observed during in vitro reprogramming before pluripotency and throughout embryogenesis. Conversely, our method reveals a significant age increase after in vivo reprogramming. We recommend including uncertainty estimation in future aging clock models to avoid the risk of misinterpreting the results of biological age prediction.