Aging Cell最新文献

Acylcarnitine (ACar) is a novel fuel source for activating thermogenesis in brown adipose tissue (BAT). However, whether ACar metabolism underlies BAT thermogenesis decline with aging remain unclear. Here, the L-carnitine-treated young and aging mice were used to investigate the effects of activation of ACar metabolism on BAT thermogenesis during aging. We showed that long term L-carnitine feeding, which results in an elevation in circulating ACar levels, failed to improve cold sensitivity of aging mice, which still displayed impaired thermogenesis and ACar metabolism in interscapular BAT (iBAT). The RNA-sequencing was used to identify the key regulator for the response of aging mice to LCar induced activation of ACar metabolism in BAT, and we identified Sirt3 as a key regulator for the response of aging mice to L-carnitine induced activation of ACar metabolism in iBAT. Then the adipose-specific Sirt3 knockout (Sirt3 AKO) mice were used to investigate the role of Sirt3 in ACar metabolism and thermogenesis of BAT and explore the underlying mechanism, and the results showed that Sirt3 AKO mice displayed defective ACar metabolism and thermogenesis in iBAT. Mechanically, Sirt3 regulated ACar metabolism via HIF1α-PPARα signaling pathway to promote iBAT thermogenesis, and knockdown or inhibition of HIF1α ameliorated impaired ACar metabolism and thermogenesis of iBAT in the absence of Sirt3. Collectively, we propose that Sirt3 regulated ACar metabolism is critical in maintaining thermogenesis in BAT of aging mice, which can promote the development of anti-aging intervention strategy.

Coronavirus disease 2019 (COVID-19) has been suggested to increase the risk of memory decline and Alzheimer's disease (AD), the main cause of dementia in the elderly. However, direct evidence about whether COVID-19 induces AD-like neuropathological changes in the brain, especially post recovery from acute infection, is still lacking. Here, using postmortem human brain samples, we found abnormal accumulation of hyperphosphorylated tau protein in the hippocampus and medial entorhinal cortex within 4–13 months post clinically recovery from acute COVID-19, together with prolonged activation of glia cells and increases in inflammatory factors, even though no SARS-COV-2 invasion was detected in these regions. By contrast, COVID-19 did not change beta-amyloid deposition and hippocampal neuron number, and had limited effects on AD-related pathological phenotypes in olfactory circuits including olfactory bulb, anterior olfactory nucleus, olfactory tubercle, piriform cortex and lateral entorhinal cortex. These results provide neuropathological evidences linking COVID-19 with prognostic increase of risk for AD.

Mesenchymal stromal cells (MSCs), also known as fibro-adipogenic progenitors, play a critical role in muscle maintenance and sarcopenia development. Although analogous MSCs are present in various tissues, recent single-cell RNA-seq studies have revealed the inter-tissue heterogeneity of MSCs. However, the functional significance of MSC heterogeneity and its role in aging remain unclear. Here, we investigated the properties of MSCs and their age-related changes in seven mouse tissues through histological, cell culture, and genetic examinations. The tissue of origin had a greater impact on the MSC transcriptome than aging. By first analyzing age-related changes, we found that Kera is exclusively expressed in muscle MSCs and significantly down-regulated by aging. Kera knockout mice recapitulated some sarcopenic phenotypes including reduced muscle mass and specific force, revealing the functional importance of Kera in the maintenance of muscle youth. These results suggest that MSCs have tissue-specific supportive functions and that deterioration in these functions may trigger tissue aging.

The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age (GrimAge, PhenoAge, IEAA, and HannumAge) (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6618–482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (IVW beta = −0.309, 95% CI: −0.38 to −0.24, p = 1.51E-19). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = −0.10, 95% CI: −0.188 to −0.013, p = 0.02). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD. In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.

Aging and, in particular, the emergence of age-related disorders is associated with tissue dysfunction and macromolecular damage, some of which can be attributable to accumulated oxidative damage. In the current study, we determine the potential of ‘plasma-derived fraction (E5)’ for cellular rejuvenation and extending the lifespan of Sprague Dawley (SD) rats. This is a unique study wherein we have used 24-month-old rats and monitored them until the end of their lifespan with and without E5 treatment. In the present investigation, the SD rats were separated into two groups old control group and the treatment group (n = 8). The treatment group received four injections of E5 every alternate day for 8 days, and eight injections every alternate day for 16 days. Body weight, grip strength, cytokines, and biochemical markers were measured for more than 400 days of the study. Clinical observation, necropsy, and histology were performed. The E5 treatment exhibited great potential by showing significantly improved grip strength, remarkably decreased pro-inflammatory markers of chronic inflammation and oxidative stress, as well as biomarkers for vital organs (BUN, SGPT, SGOT, and triglycerides), and increased anti-oxidant levels. Clinical examinations, necropsies, and histopathology revealed that the animals treated with the E5 had normal cellular structure and architecture. In conclusion, this unique ‘plasma-derived exosome’ treatment (E5) alone is adequate to improve the health-span and extend the lifespan of the old SD rats significantly.

In response to peroxynitrite (ONOO⁻) generation, myogenic stem satellite cell activator HGF (hepatocyte growth factor) undergoes nitration of tyrosine residues (Y198 and Y250) predominantly on fast IIa and IIx myofibers to lose its binding to the signaling receptor c-met, thereby disturbing muscle homeostasis during aging. Here we show that rat anti-HGF monoclonal antibody (mAb) 1H41C10, which was raised in-house against a synthetic peptide FTSNPEVR_nitroY₁₉₈EV, a site well-conserved in mammals, functions to confer resistance to nitration dysfunction on HGF. 1H41C10 was characterized by recognizing both nitrated and non-nitrated HGF with different affinities as revealed by Western blotting, indicating that the paratope of 1H41C10 may bind to the immediate vicinity of Y198. Subsequent experiments showed that 1H41C10-bound HGF resists peroxynitrite-induced nitration of Y198. A companion mAb-1H42F4 presented similar immuno-reactivity, but did not protect Y198 nitration, and thus served as the control. Importantly, 1H41C10-HGF also withstood Y250 nitration to retain c-met binding and satellite cell activation functions in culture. The Fab region of 1H41C10 exerts resistivity to Y250 nitration possibly due to its localization in the immediate vicinity to Y250, as supported by an additional set of experiments showing that the 1H41C10-Fab confers Y250-nitration resistance which the Fc segment does not. Findings highlight the in vitro preventive impact of 1H41C10 on HGF nitration-dysfunction that strongly impairs myogenic stem cell dynamics, potentially pioneering cogent strategies for counteracting or treating age-related muscle atrophy with fibrosis (including sarcopenia and frailty) and the therapeutic application of investigational HGF drugs.

Skin aging has been associated with the onset of various skin issues, and recent studies have identified an increase in Cdc42 activity in naturally aging mice. While previous literature has suggested that CASIN, a specific inhibitor of Cdc42 activity, may possess anti-aging properties, its specific effects on the epidermis and dermis, as well as the underlying mechanisms in naturally aging mice, remain unclear. Our study revealed that CASIN demonstrated the ability to increase epidermal and dermal thickness, enhance dermal-epidermal junction, and stimulate collagen and elastic fiber synthesis in 9-, 15-, and 24-month-old C57BL/6 mice in vivo. Moreover, CASIN was found to enhance the proliferation, differentiation, and colony formation and restore the cytoskeletal morphology of primary keratinocytes in naturally aging skin in vitro. Furthermore, the anti-aging properties of CASIN on primary fibroblasts in aging mice were mediated by the ribosomal protein RPL4 using proteomic sequencing, influencing collagen synthesis and cytoskeletal morphology both in vitro and in vivo. Meanwhile, both subcutaneous injection and topical application exhibited anti-aging effects for a duration of 21 days. Additionally, CASIN exhibited anti-inflammatory properties, while reduced expression of RPL4 was associated with increased inflammation in the skin of naturally aging mice. Taken together, our results unveil a novel function of RPL4 in skin aging, providing a foundational basis for future investigations into ribosomal proteins. And CASIN shows promise as a potential anti-aging agent for naturally aging mouse skin, suggesting potential applications in the field.

Aging is associated with decreased health span, and despite the recent advances made in understanding the mechanisms of aging, no antiaging drug has been approved for therapy. Therefore, strategies to promote a healthy life in aging are desirable. Previous work has shown that chronic treatment with extracellular vesicles (EVs) from young mice prolongs lifespan in old mice, but the mechanism of action of this effect on liver metabolism is not known. Here we investigated the role of treatment with EVs derived from young sedentary (EV-C) or exercised (EV-EX) mice in the metabolism of old mice and aimed to identify key youthful-associated microRNA (miRNA) cargos that could promote healthy liver function. We found that aged mice treated with either EV-C or EV-EX had higher insulin sensitivity, higher locomotor activity resulting in longer distance traveled in the cage, and a lower respiratory exchange ratio compared to mice treated with EVs from aged mice (EV-A). In the liver, treatment with young-derived EVs reduced aging-induced liver fibrosis. We identified miR-30c in the EVs as a possible youth-associated miRNA as its level was higher in circulating EVs of young mice. Treatment of aged mice with EVs transfected with miR-30c mimic reduced stellate cell activation in the liver and reduced fibrosis compared to EV-negative control by targeting Foxo3. Our results suggest that by delivering juvenile EVs to old mice, we can improve their liver health. Moreover, we identified miR-30c as a candidate for antiaging liver therapy.

Cover legend: The cover image is based on the Article HIF-1α-induced expression of the m6A reader YTHDF1 inhibits the ferroptosis of nucleus pulposus cells by promoting SLC7A11 translation by Xiao Lu et al., https://doi.org/10.1111/acel.14210

Cover legend: The cover image is based on the Article Single-neuron analysis of aging-associated changes in learning reveals impairments in transcriptional plasticity by Kerriann K. Badal et al., https://doi.org/10.1111/acel.14228 Image Credit: Phillip Gillette and Lynne Fieber