Longevity Papers

Age-related changes initiate a cascade of cellular and molecular alterations that lead to immune system dysfunction or abnormal activation, predisposing individuals to age-related diseases. This phenomenon, commonly referred to as immunosenescence, highlighting aging-associated progressive decline of the immune system. Moreover, mounting evidence suggests that immunosenescence contributes to a related pathological phenomenon known as inflammaging. Inflammaging refers to chronic, low-grade, and systemic inflammation associated with aging, occurring despite the absence of overt stimuli. In the body, inflammation is typically activated in response to overt stimuli such as bacterial/microbial invasion or a pathological state, however, inflammaging occurrence and its underpinning mechanisms seem to be independent and in the absence of such stimuli. Despite recent advancements in molecular characterization and the scrutiny of disease relevance, these two interconnected concepts have remained largely unexplored and unrecognized. In this comprehensive review, we aim to shed light on the mechanistic and cellular aspects of immunosenescence and inflammaging, as well as their pivotal roles in the pathogenesis of aging-related diseases, including cancer, infections, dementia, and neurodegenerative disorders.

Retrotransposons are self-replicating genomic elements that move from one genomic location to another using a "copy-and-paste" method involving RNA intermediaries. One family of retrotransposon that has garnered considerable attention for its association with age-related diseases and anti-aging interventions is the short interspersed nuclear elements (SINEs). This review summarizes current knowledge on the roles of SINEs in aging processes and therapies. To underscore the significant research on the involvement of SINEs in aging-related diseases, we commence by outlining compelling evidence on the classification and mechanism, highlighting implications in age-related phenomena. The intricate relationship between SINEs and diseases such as neurodegenerative disorders, heart failure, high blood pressure, atherosclerosis, type 2 diabetes mellitus, osteoporosis, visual system dysfunctions, and cancer is explored, emphasizing their roles in various age-related diseases. Recent investigations into the anti-aging potential of SINE-targeted treatments are examined, with particular attention to how SINE antisense RNA mitigate age-related alterations at the cellular and molecular levels, offering insights into potential therapeutic targets for age-related pathologies. This review aims to compile the most recent advances on the multifaceted roles of SINE retrotransposons in age-related diseases and anti-aging interventions, providing valuable insights into underlying mechanisms and therapeutic avenues for promoting healthy aging.

The aging process is a complex phenomenon characterised by a gradual decline in physiological functions and an increased susceptibility to age-related diseases. An important factor in aging is mitochondrial dysfunction, which leads to an accumulation of cellular damage over time. Mitochondrial Sirtuin 3 (Sirt3), an important regulator of energy metabolism, plays a central role in maintaining mitochondrial function. Loss of Sirt3 can lead to reduced energy levels and an impaired ability to repair cellular damage, a hallmark of the aging process. In this study we investigated the impact of Sirt3 loss on mitochondrial function, metabolic responses and cellular aging processes in male and female mouse embryonic fibroblasts (MEF) exposed to etoposide-induced DNA damage, which is commonly associated with cellular dysfunction and senescence. We found that Sirt3 contributes to the sex-specific metabolic response to etoposide treatment. While male MEF exhibited minimal damage suggesting potential prior adaptation to stress due to Sirt3 loss, female MEF lacking Sirt3 experienced higher vulnerability to genotoxic stress, implying a pivotal role of Sirt3 in their resistance to such challenges. These findings offer potential insights into therapeutic strategies targeting Sirt3- and sex-specific signalling pathways in diseases associated with DNA damage that play a critical role in the aging process.

Autophagy, as an essential physiological process in eukaryotes, has been revealed to be closely related to aging and many major diseases. Real-time in situ imaging of autophagy processes in living cells is necessary for timely detection of autophagy defects and the development of treatment methods. Currently, many studies are dedicated to the design of autophagy probes, and various types of fluorescent probes for autophagy detection have been reported. However, most of them are single fluorescence signal outputs, which may lead to non-specific signals. Nowadays a reliable and sensitive autophagy monitoring probe is still essential.

ARC (Age-related cataract) is one of the leading causes of vision impairment and blindness; however, its pathogenesis remains unclear. FYCO1 (FYVE and coiled-coil domain containing 1) serves as an autophagy adaptor. The present study investigated the role of FYCO1 in cataract.

The relationship between third-hand smoke (THS) exposure and lifespan remains inadequately explored. Our study sought to clarify the effects of THS on aging and lifespan. In this pursuit, our cross-sectional analysis assessed hematological aging markers in 986 non-smokers and examined lifespan alterations using a Drosophila model. THS exposure levels were quantified through survey metrics consistent with the Global Adult Tobacco Survey. The findings revealed that THS exposure significantly accelerated biological aging, with exposed individuals exhibiting an average increase in biological age of 3.04 years compared to their unexposed counterparts (p < 0.05). Correspondingly, the Drosophila model reflected these outcomes, showing a reduction in lifespan by 16.07 days (p < 0.01). Proteomic analyses identified MRPL2 as a pivotal protein in THS-induced aging, linking its expression to mitochondrial dysfunction and oxidative stress. Further metabolomic profiling highlighted disruptions in energy metabolism pathways. Follow-up in vitro experiments confirmed the role of MRPL2 in the aging processes at the cellular level. Overall, our results indicate that THS exposure is a significant accelerant of aging, providing new perspectives on the health consequences of environmental smoke residues.

Despite the different conditions, frailty and sarcopenia overlap regarding their common link: the assessment of walking speed and muscle strength. This study aimed to compare the frailty phenotype to the sarcopenia using different cut-off points for low grip strength to determine which better identifies mortality risk over a 14-year follow-up period.

Drosophila NF-κB transcription factor Dif has been well known for its function in innate immunity, and recent study also reveals its role in neuronal cells. However, the underlying mechanisms of Dif in the brain remain elusive. In this study, we aim to investigate the function of Dif in Drosophila brain development and how Dif regulates structure and plasticity of the brain to affect aging and behaviors. Based on the analysis of differentially expressed genes, we identified key genes associated with cell division, development and aging in the brain of Dif

Cellular senescence is a cell state characterized by resistance to apoptosis and stable cell cycle arrest. Senescence was first observed in mitotic cells in vitro. Recent evidence from in vivo studies and human tissue indicates that postmitotic cells, including neurons, may also become senescent. The quiescent cell state of neurons and inconsistent descriptions of neuronal senescence across studies, however, have caused confusion in this burgeoning field. We summarize evidence demonstrating that exit from G

Usage of the phrase "biological age" has picked up considerably since the advent of aging clocks and it has become commonplace to describe an aging clock's output as biological age. In contrast to this labeling, biological age is also often depicted as a more abstract concept that helps explain how individuals are aging internally, externally, and functionally. Given that the bulk of molecular aging is tissue-specific and aging itself is a remarkably complex, multifarious process, it is unsurprising that most surveyed scientists agree that aging cannot be quantified via a single metric. We share this sentiment and argue that, just like it would not be reasonable to assume that an individual with an ideal grip strength, VO

Podocyte senescence can cause persistent podocyte injury and albuminuria in diabetic kidney disease (DKD), but the mechanism remains obscure. In this study, podocyte senescence was confirmed by immunohistochemical staining in podocytes from patients and mice with DKD. Rheb1 knockout in podocytes aggravated podocyte senescence and injury in diabetic mice, but mitigated podocyte injury in mice with podocyte-specific mTORC1 activation induced by Tsc1 deletion. In cultured podocytes, Rheb1 knockdown remarkably accelerated podocyte senescence, independent of mTORC1. Mechanistically, PDH phosphorylation in podocyte was correlated with podocyte senescence in DKD patients. Rheb1 deficiency decreased ATP, mitochondrial membrane potential and partial components of respiratory chain complex, and enhanced ROS production and PDH phosphorylation, which indicates mitochondrial dysfunction, both in vitro and in vivo. Furthermore, Rheb1 interacted with Atp5f1c, and regulated its acetylation under a high-glucose condition. Together, Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation, in an mTORC1-independent manner, which provides experimental basis for the treatment of DKD.

Fisetin, a flavonoid naturally occurring in plants, fruits, and vegetables, has recently gained attention for its potential role as a senotherapeutic agent for the treatment of age-related chronic diseases. Senotherapeutics target senescent cells, which accumulate with age and disease, in both circulating immune cell populations and solid organs and tissues. Senescent cells contribute to development of many chronic diseases, primarily by eliciting systemic chronic inflammation through their senescence-associated secretory phenotype. Here, we explore whether fisetin as a senotherapeutic can eliminate senescent cells, and thereby alleviate chronic diseases, by examining current evidence from in vitro studies and animal models that investigate fisetin's impact on age-related diseases, as well as from phase I/II trials in various patient populations. We discuss the application of fisetin in humans, including challenges and future directions. Our review of available data suggests that targeting senescent cells with fisetin offers a promising strategy for managing multiple chronic diseases, potentially transforming future healthcare for older and multimorbid patients. However, further studies are needed to establish the safety, pharmacokinetics, and efficacy of fisetin as a senotherapeutic, identify relevant and reliable outcome measures in human trials, optimize dosing, and better understand the possible limitations of fisetin as a senotherapeutic agent.

Life expectancy and obesity prevalence are increasing worldwide, leading to an increase in the prevalence of cardiovascular disease. High-density lipoprotein (HDL) functionality and immunosenescence play key roles in cardiovascular disease, longevity, and quality of aging. Both molecular hallmarks of aging are impacted by obesity and metabolic syndrome and can be modulated by lifestyle. We aimed to evaluate the effect of a lifestyle intervention focused on an energy-reduced Mediterranean diet (erMedDiet), physical activity (PA), and behavioral support on HDL cholesterol efflux capacity (CEC) and immunosenescence.

Sarcopenia is a common age-related disease. Melatonin (MEL) is an age-related endocrine hormone, which displays a crucial role in resisting oxidative stress during aging. Importantly, the antioxidant properties of MEL can be mediated by mitochondria.

Periodontitis seriously affects oral health worldwide. Despite extensive efforts in prevention and treatment methods over the years, the prevalence of periodontitis in the population has not decreased. DNA damage-induced cellular senescence may be one of the mechanisms underlying periodontitis.Sirtuin7 (SIRT7) has deacetylase activity and regulates a variety of biological processes, including cell proliferation, death, and DNA damage repair.Increasing evidence confirms the crucial role of SIRT7 in age-related and inflammatory diseases. However, the mechanism of action of SIRT7 in periodontitis remains unclear. Our study demonstrates that SIRT7 is downregulated in human periodontal ligament fibroblasts induced by Porphyromonas gingivalis lipopolysaccharide (Pg-LPS). Overexpression of the SIRT7 gene significantly reduces the production of senescence-related molecules P53, P21, P16, as well as inflammatory cytokines IL-1β and TNF-α stimulated by Pg-LPS. Furthermore, overexpression of the SIRT7 gene significantly decreases the phosphorylation levels of AKT and mTOR in Pg-LPS-treated hPDLFs. Conversely, SIRT7 gene knockdown exhibits opposite effects compared to overexpression in Pg-LPS-treated hPDLFs. In conclusion, our findings indicate that SIRT7 can inhibit Pg-LPS-induced senescence and consequently suppress the secretion of inflammatory cytokines through the AKT/mTOR pathway. As a result, SIRT7 could be regarded a viable pharmaceutical target for clinical periodontitis treatment.

Maximum lifespan differs greatly between species, indicating that the process of senescence is largely genetically determined. Senescence evolves in part due to antagonistic pleiotropy (AP), where selection favors gene variants that increase fitness earlier in life but promote pathology later. Identifying the biological mechanisms by which AP causes senescence is key to understanding the endogenous causes of aging and its attendant diseases. Here we argue that the frequent occurrence of AP as a property of genes reflects the presence of constraint in the biological systems that they specify. This arises particularly because the functionally interconnected nature of biological systems constrains the simultaneous optimization of coupled traits (interconnection constraints), or because individual traits cannot evolve (impossibility constraints). We present an account of aging that integrates AP and biological constraint with recent programmatic aging concepts, including costly programs, quasi-programs, hyperfunction and hypofunction. We argue that AP mechanisms of costly programs and triggered quasi-programs are consequences of constraint, in which costs resulting from hyperfunction or hypofunction cause senescent pathology. Impossibility constraint can also cause hypofunction independently of AP. We also describe how AP corresponds to Stephen Jay Gould's constraint-based concept of evolutionary spandrels, and argue that pathologies arising from AP are bad spandrels. Biological constraint is a conceptual missing link between ultimate and proximate causes of senescence, including diseases of aging.

Preservation of brain health is a worldwide priority. The traditional view is that the major threats to the ageing brain lie within the brain itself. Consequently, therapeutic approaches have focused on protecting the brain from these presumably intrinsic pathogenic processes. However, an increasing body of evidence has unveiled a previously under-recognized contribution of peripheral organs to brain dysfunction and damage. Thus, in addition to the well-known impact of diseases of the heart and endocrine glands on the brain, accumulating data suggest that dysfunction of other organs, such as gut, liver, kidney and lung, substantially affects the development and clinical manifestation of age-related brain pathologies. In this Review, a framework is provided to indicate how organ dysfunction can alter brain homeostasis and promote neurodegeneration, with a focus on dementia. We delineate the associations of subclinical dysfunction in specific organs with dementia risk and provide suggestions for public health promotion and clinical management.

Physical frailty, an age-related decline in the physiological capacity and function of various organs, is associated with higher vulnerability to unfavorable health outcomes. The mechanisms proposed for physical frailty including increased inflammation and oxidative stress are closely related to nutritional status. In addition to traditional nutritional factors such as protein malnutrition and nutrient deficiencies, emerging evidence has focused on the role of functional nutrients including polyphenols, carotenoids, probiotics, prebiotics, omega-3 long-chain polyunsaturated fatty acids (n-3 PUFAs), β-hydroxy-β-methylbutyrate (HMB), coenzyme Q10 (CoQ10), and L-carnitine in modifying the risk of physical frailty syndrome. Although several clinical trials have suggested the beneficial effects of supplementation with polyphenols, HMB, and prebiotics on frailty indices, the current evidence is still not robust to support recommendations on the routine clinical use of such functional nutrients for the management of frailty. Similarly, the association between CoQ10 and frailty was mainly assessed in observational studies, and more randomized controlled trials are needed in this regard. A limited number of studies have reported the beneficial effect of L-carnitine supplementation on frailty indices. Since carnitine is mainly found in skeletal muscle and its measurement is thus challenging due to ethical constraints, it is necessary to examine the effect of different doses of L-carnitine on frailty and its indices in future studies. A large number of interventional studies evaluated the impact of n-3 PUFA supplementation on physical frailty in the elderly and many of them reported improved physical performance following supplementation, especially when combined with resistance training programs. Although promising findings from experimental and observational studies have been reported on functional nutrients, high-quality evidence from randomized controlled trials as well as detailed mechanistic studies are still required to affirm their role in the prevention and/or treatment of physical frailty. This review aims to describe the current state of research on functional nutrients that may modify the development or prognosis of frailty syndrome.

CISD2, a 2Fe2S cluster domain-containing protein, is implicated in Wolfram syndrome type 2, longevity and cancer. CISD2 is part of a ternary complex with IP

Mitochondria are metabolic and signalling hubs that integrate a plethora of interconnected processes to maintain cell homeostasis. They are also dormant mediators of inflammation and cell death, and with aging damages affecting mitochondria gradually accumulate, resulting in the manifestation of age-associated disorders. In addition to coordinate multiple intracellular functions, mitochondria mediate intercellular and inter-organ cross talk in different physiological and stress conditions. To fulfil this task, mitochondrial signalling has evolved distinct and complex conventional and unconventional routes of horizontal/vertical mitochondrial transfer. In this regard, great interest has been focused on the ability of extracellular vesicles (EVs), such as exosomes and microvesicles, to carry selected mitochondrial cargoes to target cells, in response to internal and external cues. Over the past years, the field of mitochondrial EVs (mitoEVs) has grown exponentially, revealing unexpected heterogeneity of these structures associated with an ever-expanding mitochondrial function, though the full extent of the underlying mechanisms is far from being elucidated. Therefore, emerging subsets of EVs encompass exophers, migrasomes, mitophers, mitovesicles, and mitolysosomes that can act locally or over long-distances to restore mitochondrial homeostasis and cell functionality, or to amplify disease. This review provides a comprehensive overview of our current understanding of the biology and trafficking of MitoEVs in different physiological and pathological conditions. Additionally, a specific focus on the role of mitoEVs in aging and the onset and progression of different age-related diseases is discussed.

Neuromuscular properties decline with ageing and low-level physical activities. Alaska pollack protein (APP) is reportedly effective for improving skeletal muscular functions, even if the amount is small and exercise is not conducted. However, it is unclear whether APP intake without an exercise program affects neuromuscular dysfunction in community-dwelling adults conducting normal, everyday activities. This study aimed to investigate changes in motor unit firing properties by adding APP to daily meals in community-dwelling older adults. They were divided into an APP group or a placebo control (CON) group for randomised, double-blind treatment. Participants in APP (

Individuals exposed to discrimination may exhibit greater epigenetic age acceleration (ie, cellular indicators of premature aging) over time, but few studies have examined longitudinal changes in epigenetic age acceleration, the heterogeneity in these changes for diverse groups of youths, and contextual explanations (ie, discrimination) for differences by ethnicity or race.

Medin is a protein fragment derived from milk fat globule epidermal growth factor VIII (MFG-E8). Medin aggregates are present in the vessel wall of most subjects over 50 years of age. In this narrative review, we focus on the consequences of medin aggregation in relation to the development of dementia. Recent literature revealed medin as biomarker for dementia in CSF, specifically of a vascular subtype. Preclinical work showed that medin is associated with aging-related cerebral vascular dysfunction, vascular stiffening, hypertension, and. vascular amyloid β deposition. These findings position medin as a potential mechanistic link between aging, vascular pathology and dementia.