Biogerontology最新文献

L-lactate is a catabolite from the anaerobic metabolism of glucose, which plays a paramount role as a signaling molecule in various steps of the cell survival. Its activity, as a master tuner of many mechanisms underlying the aging process, for example in the skin, is still presumptive, however its crucial position in the complex cross-talk between mitochondria and the process of cell survival, should suggest that L-lactate may be not a simple waste product but a fine regulator of the aging/survival machinery, probably via mito-hormesis. Actually, emerging evidence is highlighting that ROS are crucial in the signaling of skin health, including mechanisms underlying wound repair, renewal and aging. The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. Physiological ROS levels are essential for cutaneous health and the wound repair process. Aberrant redox signaling activity drives chronic skin disease in elderly. On the contrary, impaired redox modulation, due to enhanced ROS generation and/or reduced levels of antioxidant defense, suppresses wound healing via promoting lymphatic/vascular endothelial cell apoptosis and death. This review tries to elucidate this issue.

The gastrointestinal (GI) barrier acts as the primary interface between humans and the external environment. It constantly faces the risk of inflammation and oxidative stress due to exposure to foreign substances and microorganisms. Thus, maintaining the structural and functional integrity of the GI barrier is crucial for overall well-being, as it helps prevent systemic inflammation and oxidative stress, which are major contributors to age-related diseases. A healthy gut relies on maintaining gut redox homeostasis, which involves several essential elements. Firstly, it requires establishing a baseline electrophilic tone and an electrophilic mucosal gradient. Secondly, the electrophilic system needs to have sufficient capacity to generate reactive oxygen species, enabling effective elimination of invading microorganisms and rapid restoration of the barrier integrity following breaches. These elements depend on physiological redox signaling mediated by electrophilic pathways such as NOX2 and the H₂O₂ pathway. Additionally, the nucleophilic arm of redox homeostasis should exhibit sufficient reactivity to restore the redox balance after an electrophilic surge. Factors contributing to the nucleophilic arm include the availability of reductive substrates and redox signaling mediated by the cytoprotective Keap1-Nrf2 pathway. Future research should focus on identifying preventive and therapeutic strategies that enhance the strength and responsiveness of GI redox homeostasis. These strategies aim to reduce the vulnerability of the gut to harmful stimuli and address the decline in reactivity often observed during the aging process. By strengthening GI redox homeostasis, we can potentially mitigate the risks associated with age-related gut dyshomeostasis and optimize overall health and longevity.

We investigated the effects of lifelong aerobic exercise and 8 months of detraining after 10 months of aerobic training on circulation, skeletal muscle oxidative stress, and inflammation in aging rats. Sprague-Dawley rats were randomly assigned to the control (CON), detraining (DET), and lifelong aerobic training (LAT) groups. The DET and LAT groups began aerobic treadmill exercise at the age of 8 months and stopped training at the 18th and 26th month, respectively; all rats were sacrificed when aged 26 months. Compared with CON, LAT remarkably decreased serum and aged skeletal muscle 4-hydroxynonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. Superoxide dismutase 2(SOD2) levels were higher in the LAT group than in the CON group in skeletal muscle. However, DET remarkably decreased SOD2 protein expression and content in the skeletal muscle and increased malondialdehyde (MDA) level compared with LAT. Compared with LAT, DET remarkably downregulated adiponectin and upregulated tumor necrosis factor alpha (TNF-α) expression, while phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and 70-kDa ribosomal protein S6 kinase (P70S6K) protein expression decreased, and that of FoxO1 and muscle atrophy F-box (MAFbX) proteins increased in the quadriceps femoris. Adiponectin and TNF-α expression in the soleus muscle did not change between groups, whereas that of AKT, mammalian target of rapamycin (mTOR), and P70S6K was lower in the soleus in the DET group than in that in the LAT group. Compared with that in the LAT group, sestrin1 (SES1) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression in the DET group was lower, whereas Keap1 mRNA expression was remarkably upregulated in the quadriceps femoris. Interestingly, the protein and mRNA levels of SES1, Nrf2, and Keap1 in soleus muscle did not differ between groups. LAT remarkably upregulated ferritin heavy polypeptide 1(FTH), glutathione peroxidase 4(GPX4), and solute carrier family 7member 11 (SLC7A11) protein expression in the quadriceps femoris and soleus muscles, compared with CON. However, compared with LAT, DET downregulated FTH, GPX4, and SLC7A11 protein expression in the quadriceps femoris and soleus muscles. Long-term detraining during the aging phase reverses the improvement effect of lifelong exercise on oxidative stress, inflammation, ferroptosis, and muscle atrophy in aging skeletal muscle. The quadriceps femoris is more evident than the soleus, which may be related to the different changes in the Keap1/Nrf2 pathway in different skeletal muscles.

SARS-Cov-2 infection, which has caused the COVID-19 global pandemic, triggers cellular senescence. In this study, we investigate the role of the SARS-COV-2 spike protein (S-protein) in regulating the senescence of RPE cells. The results showed that administration or overexpression of S-protein in ARPE-19 decreased cell proliferation with cell cycle arrest at the G1 phase. S-protein increased SA-β-Gal positive ARPE-19 cells with high expression of P53 and P21, senescence-associated inflammatory factors (e.g., IL-1β, IL-6, IL-8, ICAM, and VEGF), and ROS. Elimination of ROS by N-acetyl cysteine (NAC) or knocking down p21 by siRNA diminished S-protein-induced ARPE cell senescence. Both administrated and overexpressed S-protein colocalize with the ER and upregulate ER-stress-associated BIP, CHOP, ATF3, and ATF6 expression. S-protein induced P65 protein nuclear translocation. Inhibition of NF-κB by bay-11-7082 reduced S-protein-mediated expression of senescence-associated factors. Moreover, the intravitreal injection of S-protein upregulates senescence-associated inflammatory factors in the zebrafish retina. In conclusions, the S-protein of SARS-Cov-2 induces cellular senescence of ARPE-19 cells in vitro and the expression of senescence-associated cytokines in zebrafish retina in vivo likely by activating ER stress, ROS, and NF-κb. These results may uncover a potential association between SARS-cov-2 infection and development of AMD.

In spite of considerable progress that has been reached in understanding how reactive oxygen species (ROS) interact with its cellular targets, several important challenges regarding regulatory effects of redox signaling mechanisms remain to be addressed enough in aging and age-related disorders. Redox signaling is precisely regulated in different tissues and subcellular locations. It modulates the homeostatic balance of many regulatory facilities such as cell cycle, circadian rhythms, adapting the external environments, etc. The newly proposed term "adaptive redox homeostasis" describes the transient increase in ROS buffering capacity in response to amplified ROS formation rate within a physiological range. Redox-dependent second messengers are generated in subcellular locations according to a specific set of rules and regulations. Their appearance depends on cellular needs in response to variations in external and internal stimulus. The intensity and magnitude of ROS signaling determines its downstream effects. This issue includes review and research papers in the context of redox signaling mechanisms and related redox-regulatory interventions, aiming to guide for understanding the degenerative processes of biological ageing and alleviating possible prevention approaches for age-related complications.

Bone marrow mesenchymal stem cells (BM-MSCs) have a momentous function in the composition of the bone marrow microenvironment because of their many valuable properties and abilities, such as immunomodulation and hematopoiesis. The features and actions of MSCs are influenced by senescence, which may be affected by various factors such as nutritional/micronutrients status, e.g., vitamin D. This study aimed to examine the effects of a high-calorie diet (HCD) with/without vitamin D on BM-MSCs senescence. In the first phase, 48 middle-aged rats were fed a normal chow diet (NCD, n = 24) and an HCD (n = 24) for 26 weeks. Afterward, the rats in each group were randomly divided into three equal subgroups. Immediately, eight-rat from each diet group were sacrificed to assess the HCD effects on the first phase measurements. In the second phase, the remaining 4 groups of rats were fed either NCD or HCD with (6 IU/g) or without vitamin D (standard intake: 1 IU/g); in other words, in this phase, the animals were fed (a) NCD, (b) NCD plus vitamin D, (c) HCD, and (d) HCD plus vitamin D for 4 months. BM-MSCs were isolated and evaluated for P16^INK4a, P38 MAPK, and Bmi-1 gene expression, reactive oxygen species (ROS) levels, SA-β-gal activity, and cell cycle profile at the end of both phases. After 26 weeks (first phase), the ROS level, SA-β-gal-positive cells, and cells in the G1 phase were significantly higher in HCD-fed rats than in NCD-fed ones (P < 0.05). HCD prescription did not significantly affect cells in the S and G2 phases (p > 0.05). Compared with the NCD-fed animals, P16^INK4a and P38 MAPK gene expression were up-regulated in the HCD-fed animals; also, Bmi-1 gene expression was down-regulated (P < 0.05). BM-MSCs from vitamin D-treated rats (second phase) exhibited reduced mRNA levels of P16^INK4a and P38 MAPK genes and increased Bmi-1 mRNA levels (all P < 0.05). Vitamin D prescription also declined the percentage of SA-β-gal-positive cells, ROS levels, and the cells in the G1 phase and increased the cells in the S phase in both NCD and HCD-fed animals (P < 0.05). The reduction of the cells in the G2 phase in rats fed with an NCD plus vitamin D was statistically non-significant (P = 0.128) and significant in HCD plus vitamin D rats (P = 0.002). HCD accelerates BM-MSCs senescence, and vitamin D reduces BM-MSCs senescence biomarkers.

Atherosclerosis threatens human health by developing cardiovascular diseases, the deadliest disease world widely. The major mechanism contributing to the formation of atherosclerosis is mainly due to vascular endothelial cell (VECs) senescence. We have shown that 17β-estradiol (17β-E₂) may protect VECs from senescence by upregulating autophagy. However, little is known about how 17β-E₂ activates the autophagy pathway to alleviate cellular senescence. Therefore, the aim of this study is to determine the role of estrogen receptor (ER) α and β in the effects of 17β-E₂ on vascular autophagy and aging through in vitro and in vivo models. Hydrogen peroxide (H₂O₂) was used to establish Human Umbilical Vein Endothelial Cells (HUVECs) senescence. Autophagy activity was measured through immunofluorescence and immunohistochemistry staining of light chain 3 (LC3) expression. Inhibition of ER activity was established using shRNA gene silencing and ER antagonist. Compared with ER-β knockdown, we found that knockdown of ER-α resulted in a significant increase in the extent of HUVEC senescence and senescence-associated secretory phenotype (SASP) secretion. ER-α-specific shRNA was found to reduce 17β-E₂-induced autophagy, promote HUVEC senescence, disrupt the morphology of HUVECs, and increase the expression of Rb dephosphorylation and SASP. These in vitro findings were found consistent with the in vivo results. In conclusion, our data suggest that 17β-E₂ activates the activity of ER-α and then increases the formation of autophagosomes (LC3 high expression) and decreases the fusion of lysosomes with autophagic vesicles (P62 low expression), which in turn serves to decrease the secretion of SASP caused by H₂O₂ and consequently inhibit H₂O₂-induced senescence in HUVEC cells.

Aging accompanied by several age-related complications, is a multifaceted inevitable biological progression involving various genetic, environmental, and lifestyle factors. The major factor in this process is oxidative stress, caused by an abundance of reactive oxygen species (ROS) generated in the mitochondria and endoplasmic reticulum (ER). ROS and RNS pose a threat by disrupting signaling mechanisms and causing oxidative damage to cellular components. This oxidative stress affects both the ER and mitochondria, causing proteopathies (abnormal protein aggregation), initiation of unfolded protein response, mitochondrial dysfunction, abnormal cellular senescence, ultimately leading to inflammaging (chronic inflammation associated with aging) and, in rare cases, metastasis. RONS during oxidative stress dysregulate multiple metabolic pathways like NF-κB, MAPK, Nrf-2/Keap-1/ARE and PI3K/Akt which may lead to inappropriate cell death through apoptosis and necrosis. Inflammaging contributes to the development of inflammatory and degenerative diseases such as neurodegenerative diseases, diabetes, cardiovascular disease, chronic kidney disease, and retinopathy. The body's antioxidant systems, sirtuins, autophagy, apoptosis, and biogenesis play a role in maintaining homeostasis, but they have limitations and cannot achieve an ideal state of balance. Certain interventions, such as calorie restriction, intermittent fasting, dietary habits, and regular exercise, have shown beneficial effects in counteracting the aging process. In addition, interventions like senotherapy (targeting senescent cells) and sirtuin-activating compounds (STACs) enhance autophagy and apoptosis for efficient removal of damaged oxidative products and organelles. Further, STACs enhance biogenesis for the regeneration of required organelles to maintain homeostasis. This review article explores the various aspects of oxidative damage, the associated complications, and potential strategies to mitigate these effects.

Aging-related skin diseases are gradually increasing due to the imbalance of cutaneous homeostasis in the aging population. Skin aging-induced inflammation promotes systemic inflammation and may lead to whole-body aging. Lymphatic vessels play an important role in maintaining fluid and homeostasis balance. In intrinsically aged skin, the number of lymphatic vessels decrease and their functions decline, which is related to the reduced adhesion junctions between lymphatic endothelial cells, particularly VE-cadherin. VEGFC/VEGFR-3 signal pathway plays an important role in remodeling and expansion of lymphatic vessels; the downregulation of this pathway contributes to the dysfunction of lymphatic vessels. Meanwhile, we proposed some additional mechanisms. Decline of the pumping activity of lymphatic vessels might be related to age-related changes in extracellular matrix, ROS increase, and eNOS/iNOS disturbances. In extrinsically aged skin, the hyperpermeability of lymphatic vessels results from a decrease in endothelial-specific tight junction molecules, upregulation of VEGF-A, and downregulation of the VEGFC/VEGFR-3 signaling pathway. Furthermore, some of the Phyto therapeutics could attenuate skin aging by modulating the lymphatic vessels. This review summarized the lymphatic vessel dysfunction in skin aging and anti-aging strategies based on lymphatic vessel modulation.

Aging-induced neurodegenerative diseases (NDs) are significantly increasing health problem worldwide. It has been well documented that oxidative stress is one of the potential causes of aging and age-related NDs. There are no drugs for the treatment of NDs, therefore there is an immediate necessity for the development of strategies/treatments either to prevent or cure age-related NDs. Caloric restriction (CR) and intermittent fasting have been considered as effective strategies in increasing the healthspan and lifespan, but it is difficult to adhere to these routines strictly, which has led to the development of calorie restriction mimetics (CRMs). CRMs are natural compounds that provide similar molecular and biochemical effects of CR, and activate autophagy process. CRMs have been reported to regulate redox signaling by enhancing the antioxidant defense systems through activation of the Nrf2 pathway, and inhibiting ROS generation through attenuation of mitochondrial dysfunction. Moreover, CRMs also regulate redox-sensitive signaling pathways such as the PI3K/Akt and MAPK pathways to promote neuronal cell survival. Here, we discuss the neuroprotective effects of various CRMs at molecular and cellular levels during aging of the brain. The CRMs are envisaged to become a cornerstone of the pharmaceutical arsenal against aging and age-related pathologies.