Despite extensive studies at the genomic, transcriptomic and metabolomic levels, the underlying mechanisms regulating longevity are incompletely understood. Post-translational protein acetylation is suggested to regulate aspects of longevity. To further explore the role of acetylation, we develop the PHARAOH computational tool based on the 100-fold differences in longevity within the mammalian class. Analyzing acetylome and proteome data across 107 mammalian species identifies 482 and 695 significant longevity-associated acetylated lysine residues in mice and humans, respectively. These sites include acetylated lysines in short-lived mammals that are replaced by permanent acetylation or deacetylation mimickers, glutamine or arginine, respectively, in long-lived mammals. Conversely, glutamine or arginine residues in short-lived mammals are replaced by reversibly acetylated lysine in long-lived mammals. Pathway analyses highlight the involvement of mitochondrial translation, cell cycle, fatty acid oxidation, transsulfuration, DNA repair and others in longevity. A validation assay shows that substituting lysine 386 with arginine in mouse cystathionine beta synthase, to attain the human sequence, increases the pro-longevity activity of this enzyme. Likewise, replacing the human ubiquitin-specific peptidase 10 acetylated lysine 714 with arginine as in short-lived mammals, reduces its anti-neoplastic function. Overall, in this work we propose a link between the conservation of protein acetylation and mammalian longevity.

Sarcopenia, closely associated with other diseases such as diabetes, metabolic syndrome, and osteoporosis, significantly impacts aging populations. It is characterized by muscle atrophy, increased intramuscular adipose tissue, impaired myogenesis, chronic low-grade inflammation, and reduced muscle function. The mechanisms behind aging muscle remain incompletely understood. This study aims to elucidate the role of Sirt2 in the aging process of skeletal muscles and enhance our understanding of the underlying mechanisms. Sirt2 expression was reduced in aging muscle of male mice by 40%, compared to young muscle. Aged male Sirt2 knockout mice exhibit increased intramuscular adipose tissue infiltration by 8.5-fold changes. Furthermore, the deletion of Sirt2 exacerbated myogenesis impairment in aged muscle by decreasing the expression of Pax7 (50%) and NogoA (80%), compared to age- and sex- matched counterparts, emphasizing the role of Sirt2 in pathology of aging muscle. Additionally, long-term Sirt2 deletion affected other Sirtuin subfamily members, with decreased expressions of Sirt1 (65%), Sirt4 (94%), and Sirt5 (71%), and increased expressions of Sirt6 (4.6-fold) and Sirt7 (2.8-fold) in old male Sirt2 knockout mice, while there was no difference of these gene expression in young male mice. This study underscores the critical need for a deeper investigation into Sirt2, promising new insights that could lead to targeted therapies for sarcopenia, ultimately improving the quality of life in the elderly.

Neurodegenerative diseases of the eye such as optic neuritis (ON) are hallmarked by retinal ganglion cell (RGC) loss and optic nerve degeneration leading to irreversible blindness. Therapeutic interventions enhancing expression or activity of SIRT1, an NAD+-dependent deacetylase, support, at least in part, survival of RGCs in the face of injury. Herein, we used mice with experimental autoimmune encephalomyelitis (EAE) which recapitulates axonal and neuronal damages characteristic of ON to identify gene regulatory networks affected by constitutive ubiquitous Sirt1 expression in SIRT1 knock-in mice and wild-type mice upon targeted adeno-associated virus (AAV)-mediated SIRT1 expression in RGCs. RNA seq data analysis showed that the most upregulated genes in EAE mouse retinas include those involved in inflammation, immune response, apoptosis, and mitochondrial turnover. The latter includes genes regulating mitophagy (e.g., Atg4), mitochondrial transport (e.g., Ipo- 6, Xpo- 6), and mitochondrial localization (e.g., Chrna4, Scn9a). The constitutive or RGC-targeted SIRT1 overexpression in EAE mice upregulated the expression of non-mitochondrial genes such as Ecel1 and downregulated the expression of mitophagy genes (e.g., Atg2b, Arifip1) which were upregulated by EAE alone. Thus, SIRT1 induces neuroprotection by, at least in part, balancing mitochondrial biogenesis and mitophagy and/or enhancing mitochondrial self-repair to preserve the bioenergetic capacity of RGCs.

Skeletal muscle aging, characterized by progressive declines in muscle mass and strength, correlates with reduced quality of life and increased mortality. Resistance exercise is known to be critical for maintaining skeletal muscle health. This study investigated the effects of aging and resistance exercise on muscle strength, physiological properties, longevity proteins, and telomere length in mice. Twenty-eight-week-old senescence-accelerated mouse prone 8 (SAMP8) mice were used as a model for muscle aging, with senescence-accelerated mouse resistant 1 (SAMR1) mice serving as healthy controls. The mice underwent a 12-week regimen of ladder-climbing training, a form of resistance exercise, performed three days per week. After the training, muscle strength and muscle weight were measured. Levels of the longevity proteins adenosine monophosphate-activated kinase (AMPK), mammalian target of rapamycin (mTOR), and sirtuin 1 (SIRT1) were assessed via western blotting, and telomere length was evaluated by qPCR. SAMP8 mice exhibited significantly lower muscle mass and strength than SAMR1 mice, while resistance exercise attenuated these deficits in SAMP8 mice. SAMP8 mice showed elevated AMPK phosphorylation and SIRT1 levels compared to SAMR1 mice; resistance exercise normalized AMPK phosphorylation levels to approximate those of SAMR1 mice. mTOR activity was significantly reduced in SAMP8 mice but tended to be restored by resistance exercise. Telomere length remained unchanged in SAMP8 mice after resistance exercise compared to their sedentary controls. In conclusion, aging reduces muscle function and disrupts levels of longevity proteins. Resistance exercise mitigates these effects by improving muscle function and restoring molecular balance.

Sarcopenia, characterized by an age-related decline in skeletal muscle mass and function, is closely linked to vitamin D deficiency. This study examines the role of Sirtuin 1 (Sirt1) and its regulation by vitamin D in preventing sarcopenia. Utilizing wild-type, 1α-hydroxylase knockout (1α(OH)ase-/-), and Sirt1 transgenic (Sirt1Tg) 1α(OH)ase-/- mice, we investigated muscle Sirt1 levels, muscle mass, fiber type, and senescence markers. Our results demonstrated that 1,25-Dihydroxyvitamin D (1,25(OH)2D3) upregulated Sirt1 and myogenic factor MyoD1 expression in C2C12 myoblasts via VDR-mediated transcription. Sirt1 overexpression in mesenchymal stem cells (MSCs) significantly mitigated muscle mass reduction, improved fiber cross-sectional area, and increased type II fiber numbers in 1α(OH)ase-/- mice. Mechanistically, 1,25(OH)2D3 promoted muscle cell health by enhancing Sirt1 expression, which in turn reduced muscle cell senescence and the senescence-associated secretory phenotype (SASP) through decreased levels of acetylated nuclear p53 and p65, maintaining their cytoplasmic localization. Additionally, Sirt1 overexpression accelerated muscle regeneration post-injury by increasing embryonic myosin heavy chain expression and cell proliferation. These findings underscore the therapeutic potential of targeting vitamin D and Sirt1 pathways to prevent sarcopenia, suggesting that supplementation with active vitamin D and consequent Sirt1 activation could be effective strategies for managing age-related muscle wasting.

Here, we present a protocol for assessing the impact of a chemogenetic manipulation in a subpopulation of the hypothalamic neurons on aging and lifespan control using a mouse model developed specifically for this purpose. We describe steps for stereotaxic viral injection and assess inter-tissue communication between protein phosphatase 1 regulatory subunit 17 (Ppp1r17)-expressing neurons in the dorsomedial hypothalamus and white adipose tissue. We then detail procedures for lifespan measurements following chemogenetic manipulation in aged mice. For complete details on the use and execution of this protocol, please refer to Tokizane et al.1.

Aging is a dynamic process that is driven by cellular damage and disruption of homeostatic gene regulatory networks (GRNs). Traditional studies often focus on individual genes, but understanding their interplay is key to unraveling the mechanisms of aging. This review explores the gene circuits that influence longevity and highlights the role of feedback loops in maintaining cellular balance. The SIR2-HAP circuit in yeast serves as a model to explore how mutual inhibition between pathways influences aging trajectories and how engineering stable fixed points or oscillations within these circuits can extend lifespan. Feedback loops crucial for maintaining homeostasis are also reviewed, and we highlight how their destabilization accelerates aging. By leveraging systems and synthetic biology, strategies are proposed that may stabilize these loops within single cells, thereby enhancing their resilience to aging-related damage.

Age-associated reduced motivation is a hallmark of neuropsychiatric disorders in the elderly. In our rapidly aging societies, it is critical to keep motivation levels high enough to promote healthspan and lifespan. However, how motivation is reduced during aging remains unknown. Here, we used multiple mouse models to evaluate motivation and related affective states in young and old mice. We also compared the effect of social isolation, a common stressor in aged populations, to those of aging. We found that both social isolation and aging decreased motivation in mice, but that Bdnf expression in the ventral tegmental area (VTA) was selectively decreased during aging. Furthermore, VTA-specific Bdnf knockdown in young mice recapitulated reduced motivation observed in old mice. These results demonstrate that maintaining Bdnf expression in the VTA could promote motivation to engage in effortful activities and potentially prevent age-associated neuropsychiatric disorders.

Osteoarthritis (OA) is a common degenerative bone and joint disease with an unclear pathogenesis. Our study identified that the histone acetyltransferase encoded by Kat7 is upregulated in the affected articular cartilage of OA patients and in a mice model of medial meniscal instability-induced OA. Chondrocyte-specific knockdown of Kat7 expression exhibited a protective effect on articular cartilage integrity. In vitro experiments demonstrated that KAT7 promotes cartilage catabolism, inhibits cartilage anabolism, and induces chondrocyte senescence and apoptosis. Conversely, knocking down Kat7 was shown to protect chondrocyte function. Corresponding in vivo results indicated that silencing Kat7 effectively enhances cartilage anabolism, prevents articular cartilage damage, and significantly slows OA progression. Mechanistically, KAT7 activates the TLR4/NF-κB signaling pathway, and inhibition of this pathway reverses the catabolic effects and restores anabolic activity in the presence of Kat7 overexpression. Collectively, these findings confirm the critical role of KAT7 in the pathogenesis of OA and suggest that Kat7 represents a potential therapeutic target for OA treatment. KEY MESSAGES: There is a lack of clinically effective drugs for the treatment of osteoarthritis (OA). Kat7 plays a key role in the development of OA. Knocking down Kat7 expression can alleviate the progression of OA. Kat7 accelerates the progression of OA by activating the TLR4/NF-KB signaling pathway.

Female reproduction is highly sensitive to body energy stores; persistent energy deficit, as seen in anorexia or strenuous exercise, is known to suppress ovulation via ill-defined mechanisms. We report herein that hypothalamic SIRT1, a key component of the epigenetic machinery that links nutritional status and puberty onset via modulation of Kiss1, plays a critical role in the control of the preovulatory surge of gonadotropins, i.e., the hormonal trigger of ovulation, and its repression by conditions of energy deficit. Kiss1 neurons in the preoptic area, with proven roles in the control of ovulation, express Sirt1 mRNA. Reciprocal changes in hypothalamic SIRT1 content and Kiss1 expression were observed during the pre-ovulatory phase in adult female rats. Central activation of SIRT1 reduced Kiss1 expression in the rostral hypothalamus, and attenuated the preovulatory surge, while blockade of central SIRT1 augmented it. Conditions of energy deficit enhanced hypothalamic SIRT1 activity and caused suppression of the pre-ovulatory surge and ovulation, which could be rescued by central SIRT1 inhibition. In turn, virogenetic induction of SIRT1 in rostral hypothalamic Kiss1 neurons in adult female mice disrupted ovarian cyclicity and suppressed reproductive indices, despite preserved body weight. Our data document the prominent function of hypothalamic SIRT1 as a key modulator of Kiss1 neurons and the hormonal surge driving ovulation in adulthood, with a major role in its inhibition during conditions of energy insufficiency.

The hypothalamus has been recognized as a regulator of whole-body aging. Neuropeptide Y (NPY), highly abundant in the central nervous system and produced by the hypothalamus, enhances autophagy in this brain region and mediates autophagy triggered by caloric restriction, suggesting a potential role as a caloric restriction mimetic and an aging regulator. Considering that hypothalamic NPY levels decline during aging, we investigated if reestablishment of NPY levels mitigate aging phenotype, using a mouse model of premature aging - Zmpste24-/- mouse. The results show that reestablishing hypothalamic NPY levels delayed aging-associated features, including lipodystrophy, alopecia, and memory. Moreover, these results suggest that strategies that promote maintenance of hypothalamic NPY levels might be relevant to counteract aging progression and age-related deteriorations.

Aging and metabolic disorders share intricate molecular pathways, with the Forkhead box O (FOXO)- Sirtuin 1 (SIRT1) axis emerging as a pivotal regulator of cellular stress adaptation, metabolic homeostasis, and longevity. This axis integrates nutrient signaling with oxidative stress defence, modulating glucose and lipid metabolism, mitochondrial function, and autophagy to maintain cellular stability. FOXO transcription factors, regulated by SIRT1 deacetylation, enhance antioxidant defence mechanisms, activating genes such as superoxide dismutase (SOD) and catalase, thereby counteracting oxidative stress and metabolic dysregulation. Recent evidence highlights the dynamic role of reactive oxygen species (ROS) as secondary messengers in redox signaling, influencing FOXO-SIRT1 activity in metabolic adaptation. Additionally, key redox-sensitive regulators such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) interact with this pathway, orchestrating mitochondrial biogenesis and adaptive stress responses. Pharmacological interventions, including alpha-lipoic acid (ALA), resveratrol, curcumin and NAD+ precursors, exhibit therapeutic potential by enhancing insulin sensitivity, reducing oxidative burden, and restoring metabolic balance. This review synthesizes current advancements in FOXO-SIRT1 regulation, its emerging role in redox homeostasis, and its therapeutic relevance, offering insights into future strategies for combating metabolic dysfunction and aging-related diseases.

Aging is marked by a progressive decrease in physiological function and reserve capacity, which results in increased susceptibility to diseases. Understanding the mechanisms of driving aging is crucial for extending health span and promoting human longevity. Hypoxia, marked by reduced oxygen availability, has emerged as a promising area of study within aging research. This review explores recent findings on the potential of oxygen restriction to promote healthy aging and extend lifespan. While the role of hypoxia-inducible factor 1 (HIF-1) in cellular responses to hypoxia is well-established, its impact on lifespan remains complex and context-dependent. Investigations in invertebrate models suggest a role for HIF-1 in longevity, while evidence in mammalian models is limited. Hypoxia extends the lifespan independent of dietary restriction (DR), a known intervention underlying longevity. However, both hypoxia and DR converge on common downstream effectors, such as forkhead box O (FOXO) and flavin-containing monooxygenase (FMOs) to modulate the lifespan. Further work is required to elucidate the molecular mechanisms underlying hypoxia-induced longevity and optimize clinical applications. Understanding the crosstalk between HIF-1 and other longevity-associated pathways is crucial for developing interventions to enhance lifespan and healthspan. Future studies may uncover novel therapeutic strategies to promote healthy aging and longevity in human populations.

The hypothalamic neuropeptide system of orexin (hypocretin) neurons provides projections throughout the neuraxis and has been linked to sleep regulation, feeding and motivation for salient rewards including drugs of abuse. However, relatively little has been done to examine genes associated with orexin signaling and specific behavioral phenotypes in humans. Here, we tested for association of twenty-seven genes involved in orexin signaling with behavioral phenotypes in humans. We tested the full gene set, functional subsets, and individual genes involved in orexin signaling. Our primary phenotype of interest was Externalizing, a composite factor comprised of behaviors and disorders associated with reward-seeking, motivation, and behavioral regulation. We also tested for association with additional phenotypes that have been related to orexin regulation in model organism studies, including alcohol consumption, problematic alcohol use, daytime sleepiness, insomnia, cigarettes per day, smoking initiation, and body mass index. The composite set of 27 genes corresponding to orexin function was highly associated with Externalizing, as well as with alcohol consumption, insomnia, cigarettes per day, smoking initiation and BMI. In addition, all gene subsets (except the OXR2/HCRTR2 subset) were associated with Externalizing. BMI was significantly associated with all gene subsets. The "validated factors for PPOX/HCRT" and "PPOX/HCRT upregulation" gene subsets also were associated with alcohol consumption. Individually, 8 genes showed a strong association with Externalizing, 12 with BMI, 7 with smoking initiation, 3 with alcohol consumption, and 2 with problematic alcohol use, after correction for multiple testing. This study indicates that orexin genes are associated with multiple behaviors and disorders related to self-regulation in humans. This is consistent with prior work in animals that implicated orexin signaling in motivational activation induced by salient stimuli, and supports the hypothesis that orexin signaling is an important potential therapeutic target for numerous behavioral disorders.

Over the past five years, systemic NAD+ (nicotinamide adenine dinucleotide) decline has been accepted to be a key driving force of aging in the field of aging research. The original version of the NAD World concept was proposed in 2009, providing an integrated view of the NAD+-centric, systemic regulatory network for mammalian aging and longevity control. The reformulated version of the concept, the NAD World 2.0, was then proposed in 2016, emphasizing the importance of the inter-tissue communications between the hypothalamus and peripheral tissues including adipose tissue and skeletal muscle. There has been significant progress in our understanding of the importance of nicotinamide mononucleotide (NMN), a key NAD+ intermediate, and nicotinamide phosphoribosyltransferase (NAMPT), particularly extracellular NAMPT (eNAMPT). With these exciting developments, the further reformulated version of the concept, the NAD World 3.0, is now proposed, featuring multi-layered feedback loops mediated by NMN and eNAMPT for mammalian aging and longevity control.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by irreversible lung scarring with a poor prognosis. Emerging evidence has revealed that IPF is an aging-related disease, and the development of cellular senescence plays a pivotal role in persistent remodeling and fibrotic scarring, acting as a key mechanism in the pathophysiology of IPF. Exploring therapeutic strategies for modulating cellular senescence can provide crucial insights into unraveling IPF processes. Here, we have identified Nitazoxanide (NTZ), an FDA-approved antiprotozoal agent, has specific effects on inhibiting cellular senescence development. In the bleomycin and D-galactose-induced senescence model, NTZ effectively inhibits senescence associated-β-gal staining and preserves cell proliferation ability. We also found that NTZ effectively impedes senescence progression in the bleomycin-induced pulmonary fibrosis model, while mitigating the release of senescence-associated secretory phenotype and alleviating pulmonary fibrosis. The anti-senescence effect of NTZ is mechanistically dependent on the preservation of nuclear SIRT1 expression. We observed that PI3K induces a WIPI1-mediated nucleophagic degradation of SIRT1, while NTZ effectively inhibits PI3K and suppresses WIPI1 expression, thereby maintaining SIRT1 expression in the nucleus and exerting its anti-senescence function. Collectively, our research has shown that NTZ can inhibit PI3K in senescence progression, leading to the inhibition of WIPI1-mediated SIRT1 nucleophagic degradation. As a result, NTZ alleviates fibrosis by inhibiting senescence development.

As cells divide, telomeres shorten through a phenomenon known as telomere attrition, which leads to unavoidable senescence of cells. Unprotected DNA exponentially increases the odds of mutations, which can evolve into premature aging disorders and tumorigenesis. There has been growing academic and clinical interest in exploring this duality and developing optimal therapeutic strategies to combat telomere attrition in aging and cellular immortality in cancer. The purpose of this review is to provide an updated overview of telomere biology and therapeutic tactics to address aging and cancer.

We used the Rayyan platform to review the PubMed database and examined the ClinicalTrial.gov registry to gain insight into clinical trials and their results.

Cancer cells activate telomerase or utilize alternative lengthening of telomeres to escape telomere shortening, leading to near immortality. Contrarily, normal cells experience telomeric erosion, contributing to premature aging disorders, such as Werner syndrome and Hutchinson-Gilford Progeria, and (2) aging-related diseases, such as neurodegenerative and cardiovascular diseases.

The literature presents several promising therapeutic approaches to potentially balance telomere maintenance in aging and shortening in cancer. This review highlights gaps in knowledge and points to the potential of these optimal interventions in preclinical and clinical studies to inform future research in cancer and aging.

The skin, the largest organ of the human body, plays numerous essential roles, including protection against environmental hazards and the regulation of body temperature. The processes of skin homeostasis and ageing are complex and influenced by many factors, with epigenetic mechanisms being particularly significant. Epigenetics refers to the regulation of gene expression without altering the underlying DNA sequence. The dynamic nature of the skin, characterized by constant cellular turnover and responsiveness to environmental stimuli, requires precise gene activity control. This control is largely mediated by epigenetic modifications such as DNA methylation, histone modification, and regulation by non-coding RNAs. The present review endeavours to provide a comprehensive exploration and elucidation of the role of epigenetic mechanisms in regulating skin homeostasis and ageing. By integrating our current knowledge of epigenetic modifications with the latest advancements in dermatological research, we can gain a deeper comprehension of the complex regulatory networks that govern skin biology. Understanding these mechanisms also presents promising avenues for therapeutic interventions aimed at improving skin health and mitigating age-related skin conditions.

Circadian rhythm is the internal homeostatic physiological clock that regulates the 24-hour sleep/wake cycle. This biological clock helps to adapt to environmental changes such as light, dark, temperature, and behaviors. Aging, on the other hand, is a process of physiological changes that results in a progressive decline in cells, tissues, and other vital systems of the body. Both aging and the circadian clock are highly interlinked phenomena with a bidirectional relationship. The process of aging leads to circadian disruptions while dysfunctional circadian rhythms promote age-related complications. Both processes involve diverse physiological, molecular, and cellular changes such as modifications in the DNA repair mechanisms, mechanisms, ROS generation, apoptosis, and cell proliferation. This review aims to examine the role of aging and circadian rhythms in the context of lung cancer. This will also review the existing literature on the role of circadian disruptions in the process of aging and vice versa. Various molecular pathways and genes such as BMAL1, SIRT1, HLF, and PER1 and their implications in aging, circadian rhythms, and lung cancer will also be discussed.

SIRT1, a nicotinamide adenine dinucleotide (NAD +)-dependent class III histone deacetylase, exhibits a high level of expression within renal tissues. It has garnered considerable recognition for its pivotal role in modulating signaling pathways intricately linked with the aging process; however, it extends beyond this in the organism. The literature reports that SIRT1 regulates biological processes such as glucose metabolism, lipid metabolism, oxidative stress, inflammation, autophagy, endoplasmic reticulum stress, and apoptosis. Therefore, our study reviews the primary mechanisms by which SIRT1 induces kidney disease and the regulation of related signaling pathways in different models of renal disease. We also discuss commonly studied SIRT1-targeted interventional drugs reported in the literature, including inhibitors (e.g., Ex-527) and activators (e.g., resveratrol). This study aims to provide theoretical foundations and clinical insights for the development and screening of clinical drugs targeting SIRT1, aiming at enhanced scientific approaches for the prevention and treatment of kidney diseases.

Inter-organ communication (IOC) is a complex mechanism involved in maintaining metabolic homeostasis and healthy aging. Dysregulation of distinct forms of IOC is linked to metabolic derangements and age-related pathologies, implicating these processes as a potential target for therapeutic intervention to promote healthy aging. In this review, we delve into IOC mediated by hormonal signaling, circulating factors, organelle signaling, and neuronal networks and examine their roles in regulating metabolism and aging. Given the role of the hypothalamus as a high-order control center for aging and longevity, we particularly emphasize the importance of its communication with peripheral organs and pave the way for a better understanding of this critical machinery in metabolism and aging.

Dry mouth results from decreased saliva secretion due to aging or drug side effects. Decreased saliva secretion causes dryness in the oral cavity that makes swallowing difficult and increases the risk of aspiration pneumonia. There are few fundamental treatments for dry mouth. Here we investigated whether treatment of old mice with nicotinamide mononucleotide (NMN) improved factors associated with dry mouth. Young (16-week-old) and old (113-week-old) male mice were treated subcutaneously with saline or NMN (300 mg/kg) once every two days for four weeks and saliva secretion was measured. The amount of nicotinamide adenine dinucleotide (NAD+) in salivary gland tissues was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene expression in the intestinal tract and salivary glands was measured by real-time PCR. The population of cells with acetylation in the submandibular gland was quantified by immunohistological staining. SA-β-gal activity in the submandibular gland was measured to assess cell senescence. Statistical analysis was performed by one-way analysis of variance with Tukey post hoc analysis. The submandibular glands from old mice treated with NMN exhibited increased saliva secretion and NAD+ levels, which both decrease with aging. In addition, the submandibular glands from NMN-treated old mice had decreased acetylation, numbers of senescent cells, and levels of senescence-associated secretory phenotype (SASP) factors, which all increase with aging, as well as increased aquaporin5 (AQP5) mRNA expression. NMN administration may improve dry mouth by regulating cellular senescence in the submandibular gland and increasing expression of AQP5, a water channel involved in saliva secretion, to inhibit age-related decreases in saliva secretion. It is necessary to elucidate further mechanism and confirm its effectiveness in humans.

The SARS-CoV-2 pandemic has resulted in 762 million infections worldwide from 2020 to date, of which approximately ten percent are suffering from the effects after infection in 2019 (COVID-19) [1, 40]. In Germany, it is now assumed that at least one million people suffer from post-COVID condition with long-term consequences. These have been previously reported in diseases like Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS). Symptoms show a changing variability and recent surveys in the COVID context indicate that 10-30 % of outpatients, 50 to 70% of hospitalised patients suffer from sequelae. Recent data suggest that only 13% of all ill people were completely free of symptoms after recovery [3, 9]. Current hypotheses consider chronic inflammation, mitochondrial dysfunction, latent viral persistence, autoimmunity, changes of the human microbiome or multilocular sequelae in various organ system after infection. Hyperbaric oxygen therapy (HBOT) is applied since 1957 for heart surgery, scuba dive accidents, CO intoxication, air embolisms and infections with anaerobic pathogens. Under hyperbaric pressure, oxygen is physically dissolved in the blood in higher concentrations and reaches levels four times higher than under normobaric oxygen application. Moreover, the alternation of hyperoxia and normoxia induces a variety of processes at the cellular level, which improves oxygen supply in areas of locoregional hypoxia. Numerous target gene effects on new vessel formation, anti-inflammatory and anti-oedematous effects have been demonstrated [74]. The provision of intermittently high, local oxygen concentrations increases repair and regeneration processes and normalises the predominance of hyperinflammation. At present time only one prospective, randomized and placebo-controlled study exists with positive effects on global cognitive function, attention and executive function, psychiatric symptoms and pain interference. In conclusion, up to this date HBO is the only scientifically proven treatment in a prospective randomized controlled trial to be effective for cognitive improvement, regeneration of brain network and improvement of cardiac function. HBOT may have not only theoretical but also potential impact on targets of current pathophysiology of Post COVID condition, which warrants further scientific studies in patients.

Senoinflammation is characterized by an unresolved low-grade inflammatory process that affects multiple organs and systemic functions. This review begins with a brief overview of the fundamental concepts and frameworks of senoinflammation. It is widely involved in the aging of various organs and ultimately leads to progressive systemic degeneration. Senoinflammation underlying age-related inflammation, is causally related to metabolic dysregulation and the formation of senescence-associated secretory phenotype (SASP) during aging and age-related diseases. This review discusses the biochemical evidence and molecular biology data supporting the concept of senoinflammation and its regulatory processes, highlighting the anti-aging and anti-inflammatory effects of calorie restriction (CR). Experimental data from CR studies demonstrated effective suppression of various pro-inflammatory cytokines and chemokines, lipid accumulation, and SASP during aging. In conclusion, senoinflammation represents the basic mechanism that creates a microenvironment conducive to aging and age-related diseases. Furthermore, it serves as a potential therapeutic target for mitigating aging and age-related diseases.

The pursuit of extreme longevity is a popular topic. Advanced technologies such as metabolomics and proteomics have played a crucial role in unraveling complex molecular interactions and identifying novel longevity-related biomarkers in long-lived individuals. This review summarizes key longevity-related biomarkers identified through metabolomics, including high levels of omega-3 polyunsaturated fatty acids (PUFAs), short-chain fatty acids (SCFAs) and sphingolipids, as well as low levels of tryptophan. Proteomics analyses have highlighted longevity-related proteins such as apolipoprotein E (APOE) and pleiotrophin (PTN), along with lower S-nitrosylated and higher glycosylated proteins found from post-translational modification proteomics as potential biomarkers. We discuss the molecular mechanisms that could support the above biomarkers' potential for healthy longevity, including metabolic regulation, immune homeostasis maintenance, and resistance to cellular oxidative stress. Moreover, multi-omics studies of various long-lived cohorts are encompassed, focusing on how the integration of various omics technologies has contributed to the understanding of longevity. This comprehensive review aims to provide new biological insights and pave the way for promoting health span.

Despite extensive research into extending human healthspan (HS) and compressing morbidity, the mechanisms underlying aging remain elusive. However, a better understanding of the genetic advantages responsible for the exceptional HS of healthy centenarians (HC), who live in good physical and mental health for one hundred or more years, could lead to innovative health-extending strategies. This review explores the role of NLRP3, a critical component of innate immunity that significantly impacts aging. It is activated by pathogen-associated signals and self-derived signals that increase with age, leading to low-grade inflammation implicated in age-related diseases. Furthermore, NLRP3 functions upstream in several molecular aging pathways, regulates cellular senescence, and may underlie the robust health observed in HC. By targeting NLRP3, mice exhibit a phenotype akin to that of HC, the HS of monkeys is extended, and aging symptoms are reversed in humans. Thus, targeting NLRP3 could offer a promising approach to extend HS. Additionally, a paradigm shift is proposed. Given that the HS of the broader population is 30 years shorter than that of HC, it is postulated that they suffer from a form of accelerated aging. The term 'auto-aging' is suggested to describe accelerated aging driven by NLRP3.

Over the past century, age-related diseases, such as cancer, type-2 diabetes, obesity, and mental illness, have shown a significant increase, negatively impacting overall quality of life. Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels, including transcriptional, translational, and post-translational processes, resulting from cellular stress and circadian derangements. The circadian clock emerges as a key regulator, sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes, such as stem-cell function, cellular stress responses, and inter-tissue communication, which become disrupted during aging. Given the crucial role of hypothalamic circuits in regulating organismal physiology, metabolic control, sleep homeostasis, and circadian rhythms, and their dependence on these processes, strategies aimed at enhancing hypothalamic and circadian function, including pharmacological and non-pharmacological approaches, offer systemic benefits for healthy aging. Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions, like the hypothalamus, while reducing side effects associated with systemic drug delivery, thereby presenting new therapeutic possibilities for diverse age-related conditions.

Multiple organs orchestrate the maintenance of proper physiological function in organisms throughout their lifetimes. Recent studies have uncovered that aging and longevity are regulated by cell non-autonomous signaling mechanisms in several organisms. In the brain, particularly in the hypothalamus, aging and longevity are regulated by such cell non-autonomous signaling mechanisms. Several hypothalamic neurons have been identified as regulators of mammalian longevity, and manipulating them promotes lifespan extension or shortens the lifespan in rodent models. The hypothalamic structure and function are evolutionally highly conserved across species. Thus, elucidation of hypothalamic function during the aging process will shed some light on the mechanisms of aging and longevity and, thereby benefiting to human health.

Every individual at some point encounters the progressive biological process of aging, which is considered one of the major risk factors for common diseases. The main drivers of aging are oxidative stress, senescence, and reactive oxygen species (ROS). The renin-angiotensin-aldosterone system (RAAS) includes several systematic processes for the regulation of blood pressure, which is caused by an imbalance of electrolytes. During activation of the RAAS, binding of angiotensin II (ANG II) to angiotensin II type 1 receptor (AGTR1) activates intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate superoxide anions and promote uncoupling of endothelial nitric oxide (NO) synthase, which in turn decreases NO availability and increases ROS production. Promoting oxidative stress and DNA damage mediated by ANG II is tightly regulated. Individuals with sodium deficiency-associated diseases such as Gitelman syndrome (GS) and Bartter syndrome (BS) show downregulation of inflammation-related processes and have reduced oxidative stress and ROS. Additionally, the histone deacetylase sirtuin-1 (SIRT1) has a significant impact on the aging process, with reduced activity with age. However, GS/BS patients generally sustain higher levels of sirtuin-1 (SIRT1) activity than age-matched healthy individuals. SIRT1 expression in GS/BS patients tends to be higher than in healthy age-matched individuals; therefore, it can be assumed that there will be a trend towards healthy aging in these patients. In this review, we highlight the importance of the hallmarks of aging, inflammation, and the RAAS system in GS/BS patients and how this might impact healthy aging. We further propose future research directions for studying the etiology of GS/BS at the molecular level using patient-derived renal stem cells and induced pluripotent stem cells.

Aging is currently viewed as a result of multiple biological processes that manifest themselves independently, reinforce each other and in their totality lead to the aged phenotype. Genetic and pharmaceutical approaches targeting specific underlying causes of aging have been used to extend the lifespan and healthspan of model organisms ranging from yeast to mammals. However, most interventions display only a modest benefit. This outcome is to be expected if we consider that even if one aging process is successfully treated, other aging pathways may remain intact. Hence solving the problem of aging may require targeting not one but many of its underlying causes at once. Here we review the challenges and successes of combination therapies aimed at increasing the lifespan of mammals and propose novel directions for their development. We conclude that both additive and synergistic effects on mammalian lifespan can be achieved by combining interventions that target the same or different hallmarks of aging. However, the number of studies in which multiple hallmarks were targeted simultaneously is surprisingly limited. We argue that this approach is as promising as it is understudied.

Osteoporosis (OP) is a common metabolic bone disease characterized by low bone mass, decreased bone mineral density, and degradation of bone tissue microarchitecture. However, our understanding of the mechanisms of bone remodeling and factors affecting bone mass remains incomplete. Sirtuin1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase that regulates a variety of cellular metabolisms, including inflammation, tumorigenesis, and bone metabolism. Recent studies have emphasized the important role of SIRT1 in bone homeostasis. This article reviews the role of SIRT1 in bone metabolism and OP and also discusses therapeutic strategies and future research directions for targeting SIRT1.

Ageing is characterized by a gradual decline in the efficiency of physiological functions and increased vulnerability to diseases. Ageing affects the entire body, including physical, mental, and social well-being, but its impact on the brain and cognition can have a particularly significant effect on an individual's overall quality of life. Therefore, enhancing lifespan and physical health in longevity studies will be incomplete if cognitive ageing is over looked. Promoting successful cognitive ageing encompasses the objectives of mitigating cognitive decline, as well as simultaneously enhancing brain function and cognitive reserve. Studies in both humans and animal models indicate that cognitive decline related to normal ageing and age-associated brain disorders are more likely linked to changes in synaptic connections that form the basis of learning and memory. This activity-dependent synaptic plasticity reorganises the structure and function of neurons not only to adapt to new environments, but also to remain robust and stable over time. Therefore, understanding the neural mechanisms that are responsible for age-related cognitive decline becomes increasingly important. In this review, we explore the multifaceted aspects of healthy brain ageing with emphasis on synaptic plasticity, its adaptive mechanisms and the various factors affecting the decline in cognitive functions during ageing. We will also explore the dynamic brain and neuroplasticity, and the role of lifestyle in shaping neuronal plasticity.

The hypothalamus, in addition to controlling the main body's vital functions, is also involved in aging regulation. The aging process in the hypothalamus is accompanied by disturbed intracellular pathways, including Ca2+ signaling and neuronal excitability in the brain. Intrinsic electrophysiological properties of individual neurons and synaptic transmission between cells is disrupted in the central nervous system of old animals. However, changes in neuronal excitability and excitation/inhibition balance with aging are specific to the type of neurons, brain region, and species. Glia-neuron interactions play a significant role in the brain and undergo remodeling accompanied by advanced loss of function with aging. In the current review, I have summarized the current understanding of the changes in the brain and especially in the hypothalamus with aging.

Common and rare alleles are now being annotated across millions of human genomes, and omics technologies are increasingly being used to develop health and treatment recommendations. However, these alleles have not yet been systematically characterized relative to aerospace medicine. Here, we review published alleles naturally found in human cohorts that have a likely protective effect, which is linked to decreased cancer risk and improved bone, muscular, and cardiovascular health. Although some technical and ethical challenges remain, research into these protective mechanisms could translate into improved nutrition, exercise, and health recommendations for crew members during deep space missions.

Arsenic, a widespread environmental poison, can cause significant liver damage upon exposure. Mitochondria are the most sensitive organelles to external factors. Dysfunctional mitochondria play a crucial role in cellular senescence and liver damage. Tunnelling nanotubes (TNTs), membrane structures formed between cells, with fibrous actin (F-actin) serving as the scaffold, facilitate mitochondrial transfer between cells. Notably, TNTs mediate the delivery of healthy mitochondria to damaged cells, thereby mitigating cellular damage. Although limited studies have suggested that F-actin may be modulated by the longevity gene SIRT1, the association between arsenic-induced liver damage and this mechanism remains unexplored. The findings of the current study indicate that arsenic suppresses SIRT1 and F-actin in the rat liver and MIHA cells, impeding the formation of TNTs and mitochondrial transfer between MIHA cells, thereby playing a pivotal role in mitochondrial dysfunction, cellular senescence and liver damage induced by arsenic. Notably, increasing SIRT1 levels effectively mitigated liver mitochondrial dysfunction and cellular senescence triggered by arsenic, highlighting SIRT1's crucial regulatory function. This research provides novel insights into the mechanisms underlying arsenic-induced liver damage, paving the way for the development of targeted preventive and therapeutic drugs to address arsenic-induced liver damage.

Sirtuins are pivotal in orchestrating numerous cellular pathways, critically influencing cell metabolism, DNA repair, aging processes, and oxidative stress. In recent years, the involvement of sirtuins in tumor biology has garnered substantial attention, with a growing body of evidence underscoring their regulatory roles in various aberrant cellular processes within tumor environments. This article delves into the sirtuin family and its biological functions, shedding light on their dual roles-either as promoters or inhibitors-in various cancers including oral, breast, hepatocellular, lung, and gastric cancers. It further explores potential anti-tumor agents targeting sirtuins, unraveling the complex interplay between sirtuins, miRNAs, and chemotherapeutic drugs. The dual roles of sirtuins in cancer biology reflect the complexity of targeting these enzymes but also highlight the immense therapeutic potential. These advancements hold significant promise for enhancing clinical outcomes, marking a pivotal step forward in the ongoing battle against cancer.

Doxorubicin (DOX) is an anthracycline antibiotic used as an antitumor treatment. However, its clinical application is limited due to severe side effects such as cardiotoxicity. In recent years, numerous studies have demonstrated that cellular aging has become a therapeutic target for DOX-induced cardiomyopathy. However, the underlying mechanism and specific molecular targets of DOX-induced cardiomyocyte aging remain unclear. Poly (ADP-ribose) polymerase (PARP) is a family of protein post-translational modification enzymes in eukaryotic cells, including 18 members. PARP-1, the most well-studied member of this family, has become a potential molecular target for the prevention and treatment of various cardiovascular diseases, such as DOX cardiomyopathy and heart failure. PARP-1 and PARP-2 share 69% homology in the catalytic regions. However, they do not entirely overlap in function. The role of PARP-2 in cardiovascular diseases, especially in DOX-induced cardiomyocyte aging, is less studied. In this study, we found for the first time that down-regulation of PARP-2 can inhibit DOX-induced cellular aging in cardiomyocytes. On the contrary, overexpression of PARP-2 can aggravate DOX-induced cardiomyocyte aging and injury. Further research showed that PARP-2 inhibited the expression and activity of SIRT1, which in turn was involved in the development of DOX-induced cardiomyocyte aging and injury. Our findings provide a preliminary experimental basis for establishing PARP-2 as a new target for preventing and treating DOX cardiomyopathy and related drug development.

Cardiovascular diseases (CVDs) can be described as a global health emergency imploring possible prevention strategies. Although the pathogenesis of CVDs has been extensively studied, the role of mitochondrial dysfunction in CVD development has yet to be investigated. Diabetic cardiomyopathy, ischemic-reperfusion injury, and heart failure are some of the CVDs resulting from mitochondrial dysfunction Recent evidence from the research states that any dysfunction of mitochondria has an impact on metabolic alteration, eventually causes the death of a healthy cell and therefore, progressively directing to the predisposition of disease. Cardiovascular research investigating the targets that both protect and treat mitochondrial damage will help reduce the risk and increase the quality of life of patients suffering from various CVDs. One such target, i.e., nuclear sirtuin SIRT6 is strongly associated with cardiac function. However, the link between mitochondrial dysfunction and SIRT6 concerning cardiovascular pathologies remains poorly understood. Although the Role of SIRT6 in skeletal muscles and cardiomyocytes through mitochondrial regulation has been well understood, its specific role in mitochondrial maintenance in cardiomyocytes is poorly determined. The review aims to explore the domain-specific function of SIRT6 in cardiomyocytes and is an effort to know how SIRT6, mitochondria, and CVDs are related.

Our previous studies have shown that scorpion venom heat-resistant synthesized peptide (SVHRSP) induces a significant extension in lifespan and improvements in age-related physiological functions in worms. However, the mechanism underlying the potential anti-aging effects of SVHRSP in mammals remains elusive.

Following SVHRSP treatment in senescence-accelerated mouse resistant 1 (SAMR1) or senescence-accelerated mouse prone 8 (SAMP8) mice, behavioral tests were conducted and brain tissues were collected for morphological analysis, electrophysiology experiments, flow cytometry, and protein or gene expression. The human neuroblastoma cell line (SH-SY5Y) was subjected to H2O2 treatment in cell experiments, aiming to establish a cytotoxic model that mimics cellular senescence. This model was utilized to investigate the regulatory mechanisms underlying oxidative stress and neuroinflammation associated with age-related cognitive impairment mediated by SVHRSP.

SVHRSP significantly ameliorated age-related cognitive decline, enhanced long-term potentiation, restored synaptic loss, and upregulated the expression of synaptic proteins, therefore indicating an improvement in synaptic plasticity. Moreover, SVHRSP demonstrated a decline in senescent markers, including SA-β-gal enzyme activity, P16, P21, SIRT1, and cell cycle arrest. The underlying mechanisms involve an upregulation of antioxidant enzyme activity and a reduction in oxidative stress-induced damage. Furthermore, SVHRSP regulated the nucleoplasmic distribution of NRF2 through the SIRT1-P53 pathway. Further investigation indicated a reduction in the expression of proinflammatory factors in the brain after SVHRSP treatment. SVHRSP attenuated neuroinflammation by regulating the NF-κB nucleoplasmic distribution and inhibiting microglial and astrocytic activation through the SIRT1-NF-κB pathway. Additionally, SVHRSP significantly augmented Nissl body count while suppressing neuronal loss.

SVHRSP could remarkably improve cognitive deficiency by inhibiting oxidative stress and neuroinflammation, thus representing an effective strategy to improve brain health.

In contrast to the hypothesis that aging results from cell-autonomous deterioration processes, the programmed longevity theory proposes that aging arises from a partial inactivation of a "longevity program" aimed at maintaining youthfulness in organisms. Supporting this hypothesis, age-related changes in organisms can be reversed by factors circulating in young blood. Concordantly, the endocrine secretion of exosomal microRNAs (miRNAs) by hypothalamic neural stem cells (htNSCs) regulates the aging rate by enhancing physiological fitness in young animals. However, the specific molecular mechanisms through which hypothalamic-derived miRNAs exert their anti-aging effects remain unexplored. Using experimentally validated miRNA-target gene interactions and single-cell transcriptomic data of brain cells during aging and heterochronic parabiosis, we identify the main pathways controlled by these miRNAs and the cell-type-specific gene networks that are altered due to age-related loss of htNSCs and the subsequent decline in specific miRNA levels in the cerebrospinal fluid (CSF). Our bioinformatics analysis suggests that these miRNAs modulate pathways associated with senescence and cellular stress response, targeting crucial genes such as Cdkn2a, Rps27, and Txnip. The oligodendrocyte lineage appears to be the most responsive to age-dependent loss of exosomal miRNA, leading to significant derepression of several miRNA target genes. Furthermore, heterochronic parabiosis can reverse age-related upregulation of specific miRNA-targeted genes, predominantly in brain endothelial cells, including senescence promoting genes such as Cdkn1a and Btg2. Our findings support the presence of an anti-senescence mechanism triggered by the endocrine secretion of htNSC-derived exosomal miRNAs, which is associated with a youthful transcriptional signature.

Aging is defined as a progressive decline of cognitive and physiological functions over lifetime. Since the definition of the nine hallmarks of aging in 2013 by López-Otin, numerous studies have attempted to identify the main regulators and contributors in the aging process. One interesting group of proteins whose participation has been implicated in several aging hallmarks are the nuclear DBF2-related (NDR) family of serine-threonine AGC kinases. They are one of the core components of the Hippo signaling pathway and include NDR1, NDR2, LATS1 and LATS2 in mammals, along with its highly conserved metazoan orthologs; Trc in Drosophila melanogaster, SAX-1 in Caenorhabditis elegans, CBK1, DBF20 in Saccharomyces cerevisiae and orb6 in Saccharomyces pombe. These kinases have been independently linked to the regulation of widely diverse cellular processes disrupted during aging such as the cell cycle progression, transcription, intercellular communication, nutrient homeostasis, autophagy, apoptosis, and stem cell differentiation. However, a comprehensive overview of the state-of-the-art knowledge regarding the post-translational modifications of and by NDR kinases in aging has not been conducted. In this review, we summarize the current understanding of the NDR family of kinases, focusing on their relevance to various aging hallmarks, and emphasize the growing body of evidence that suggests NDR kinases are essential regulators of aging across species.

Aging is linked to a time-associated decline in both cellular function and repair capacity leading to malfunction on an organismal level, increased frailty, higher incidence of diseases, and death. As the population grows older, there is a need to reveal mechanisms associated with aging that could spearhead treatments to postpone the onset of age-associated decline, extend both healthspan and lifespan. One possibility is targeting the sirtuin SIRT1, the founding member of the sirtuin family, a highly conserved family of histone deacetylases that have been linked to metabolism, stress response, protein synthesis, genomic instability, neurodegeneration, DNA damage repair, and inflammation. Importantly, sirtuins have also been implicated to promote health and lifespan extension, while their dysregulation has been linked to cancer, neurological processes, and heart disorders. SIRT1 is one of seven members of sirtuin family; each requiring nicotinamide adenine dinucleotide (NAD+) as co-substrate for their catalytic activity. Overexpression of yeast, worm, fly, and mice SIRT1 homologs extend lifespan in each animal, respectively. Moreover, lifespan extension due to calorie restriction are associated with increased sirtuin activity. These findings led to the search for a calorie restriction mimetic, which revealed the compound resveratrol; (3, 5, 4'-trihydroxy-trans-stilbene) belonging to the stilbenoids group of polyphenols. Following this finding, resveratrol and other sirtuin-activating compounds have been extensively studied for their ability to affect health and lifespan in a variety of species, including humans via clinical studies.