Age-related Functional Decline Research Articles

The age-related decline of helicase function-how G-quadruplex structures promote genome instability.

The intricate mechanisms underlying transcription-dependent genome instability involve G-quadruplexes (G4) and R-loops. This perspective elucidates the potential link between these structures and genome instability in aging. The co-occurrence of G4 DNA and RNA-DNA hybrid structures (G-loop) underscores a complex interplay in genome regulation and instability. Here, we hypothesize that the age-related decline of sirtuin function leads to an increase in acetylated helicases that bind to G4 DNA and RNA-DNA hybrid structures, but are less efficient in resolving them. We propose that acetylated, less active, helicases induce persistent G-loop structures, promoting transcription-dependent genome instability in aging.

Hidden Dangers of Frailty: Higher Mortality, Complications and Costs in Acute Pancreatitis.

Frailty is a clinically recognizable state of increased vulnerability due to age-related decline in reserve and function across multiple physiologic systems that compromises the ability to cope with acute stress. As frailty is being identified as an important risk factor in outcomes of gastrointestinal pathologies, we aimed to assess outcomes in patients with acute pancreatitis within this cohort. We conducted a retrospective study using the Nationwide Inpatient Sample (NIS) database. ICD-10 codes were used to inquire for patients admitted with acute pancreatitis between September 2015 through 2017. ICD-10 codes corresponding to the Hospital Frailty Risk Score (HFRS) were used to divide the study sample into 2 cohorts: low risk (< 5 points) and intermediate or high risk (> 5 points). To calculate the points, we fitted a logistic regression model that included membership of the frail group as the binary dependent variable (frail vs. non-frail) and the set of ICD-10 codes as binary predictor variables (1 = present, 0 = absent for each code). To simplify the calculation and interpretation, we multiplied regression coefficients by five to create a points system, so that a certain number of points are awarded for each ICD-10 code and added together to create the final frailty risk score. Multivariate regression analysis was performed to find adjusted mortality. Out of a total of 1,267,744 patients admitted with acute pancreatitis, 728,953 (57.5%) were identified as intermediate and high risk (> 5 points) (study cohort) and 538,781 (42.5%) as low risk (< 5 points). The mean age in the study cohort was 64.8 ± 12.6 and that in the low-risk group was 58.6 ± 9.5. Most of the patients in both groups were males and Caucasians; Medicare was the predominant insurance provider. A majority of the admissions in both groups were in an urban teaching hospital and were emergency. (Table1). The primary outcome was in-hospital mortality which was significantly higher in the study cohort as compared to the low-risk group (4.3% vs. 2.5%, p < 0.0001). The age-adjusted Odds ratio of mortality was 1.72(95% CI (Confidence Interval) 1.65-1.80, p < 0.05). When compared between the two groups; median length of stay (6 vs. 4); hospitalization cost ($14,412 vs. $10,193), disposition to a skilled nursing facility (SNF) (17.1% vs. 8.6%) and need for home health care (HHC) was significantly higher in the study cohort. Complications like septicemia, septic shock, and acute kidney injury were also higher in the study group (Table2). Table1 Baseline demographics of the cohort Characteristics Acute pancreatitis with High HES Frailty score (> 5, intermediate + high) Acute pancreatitis with low HES Frailty score (< 5) P-value N = 1,267,744 N = 728,953 (57.5%) N = 538,781 (42.5%) Age Mean years (Mean ± SD) 64.8 ± 12.6 58.6 ± 9.5 < 0.001 Gender < 0.001 Male 59.1% 52.3% Female 40.9% 47.7% *Missing-475 Age groups < 0.001 18-44 3.7% 14.3% 45-64 48% 52.9% 65-84 32.2% 28.7% ≥ 85 16.1% 4.1% Race < 0.001 Caucasians 67.4% 61.9% African Americans 9.6% 16.8% Others 23% 21.3% *Missing-10 Insurance type < 0.001 Medicare 40.9% 36.3% Medicaid 17.2% 24.3% Private 31.8% 27.9% Other 9.9% 11.4% *Missing-75 Active smoking 32.7% 37.9% 0.005 Biliary Stone 36.2% 16.7% < 0.001 Admission Type < 0.001 Emergent 93.7% 94.3% Elective 6.3% 5.7% *Missing-2880 Hospital ownership/control < 0.001 Rural 7.8% 10% Urban nonteaching 26.3% 26.6% Urban teaching 65.9% 63.4% Table2 Outcomes Outcomes Acute pancreatitis with High HES Frailty score (> 5, intermediate + high) Acute pancreatitis with low HES Frailty score (< 5) P-value In-hospital mortality *Missing-920 4.3% 2.5% < .0001 1.72(1.65-1.80) < .0001 Length of stay, days (Median,IQR) 6(3-8) 4(2-6) < .0001 Total hospitalization cost, $ (Median,IQR) 14,412(8843-20,216) 10,193(6840-13,842) < .0001 In-Hospital Complications ARDS 0.4% 0.3% 0.08 Ventilator dependence respiratory failure 0.23% 0.29% 0.25 Septicemia 15.2% 9.6% < .0001 Septic Shock 6.1% 2.9% < .0001 AKI 24.8% 14.9% < .0001 Disposition < .0001 Discharge to home 58.9% 74.9% Transfer other: includes Skilled Nursing Facility (SNF), Intermediate Care Facility (ICF), and another type of facility 17.1% 8.6% Home health care 11.5% 8.1% Against medical advice (AMA) 1.6% 3.4% *Missing-920 CONCLUSION: Using frailty as a construct to identify those who are at greater risk for adverse outcomes, can help formulate interventions to target individualized reversible factors to improve outcomes in patients with acute pancreatitis. Future large-scale prospective studies are warranted to understand the dynamic and longitudinal relationship between pancreatitis and frailty.

Validation of Hospital Frailty Risk Score in Heart Failure

Background: Frailty is prevalent in older people and results from age-related decline in physiological function and reserve. The objective of this study was to validate the Hospital Frailty Risk Score (HFRS) in predicting outcomes and hospitalisation usage in older hospitalised heart failure (HF) patients. Methods: This study was a retrospective review of electronic medical records. Patients aged ≥65 years admitted with HF to a Singapore tertiary hospital between 1 January 2021 and 30 April 2021 were included. Patients were identified as HF patients in the value-driven care pathway and using ICD codes for HF. They were categorised into low risk (&lt;5), intermediate risk (5–15) and high risk (&gt;15) of frailty using the HFRS. Results: A total of 208 older patients with HF were included (mean age 79.4 years; 50.5% males). Using the HFRS, 35.1% were deemed at low risk, 46.2% at intermediate risk and 18.8% at high risk of frailty. Those at high risk of frailty were older than those at low risk (mean age 84.8 versus 76.5 years, respectively; p&lt;0.001). Women had a higher risk of frailty than men. Univariate analyses showed longer length of stay (LOS) and higher 30-, 90- and 365-day mortality in those at high frailty risk. In multivariate analyses, HFRS was associated with long LOS, 90-day and 1-year mortality. Dementia, acute MI and renal disease were more common in high-risk patients. Comparing HFRS with the Charlson Comorbidity Index (CCI), HFRS was a better predictor of long LOS, mortality at 30, 90, 1 year and 30-day readmission than CCI. HFRS alone was a better predictor than combining the HFRS and CCI. Conclusion: Older patients with higher HFRS have increased healthcare utilisation, including longer LOS and higher mortality.

MDM2 accelerated renal senescence via ubiquitination and degradation of HDAC1.

Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-β-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.

Evaluating the effects of hormone therapy termination on skeletal muscle and physical independence in postmenopausal women.

In women, the age-related decline in skeletal muscle structure and function is accelerated after menopause, which implicates the role of decreased circulating estrogen levels. Indeed, boosting estrogen, by means of postmenopausal hormone therapy (HT), generally proves beneficial to skeletal muscle. The evidence regarding whether these benefits persist even after cessation of HT is limited, nor is it clear how physical behavior (PB) impacts on benefits. Hence, this exploratory study focused on the interplay between HT administration/cessation, PB and in vivo skeletal muscle structure and function. Fifty healthy women (≥60 y) were included; 19 had an HT administration history (≥9 mo, with now ~8-y hiatus in treatment) and 31 no such history. On seven continuous days, PB data were collected using triaxial accelerometry and analyzed using compositional data analysis. Gastrocnemius medialis muscle volume, architecture, and function were determined using ultrasonography, electromyography, dual x-ray absorptiometry, and dynamometry. Current serum estradiol levels were measured using ELISA. Only fascicle length and duration of HT administration were positively associated. With respect to PB levels, we found a pattern suggesting greater vitality (higher physical activity and lower sedentarism) in previous HT users, compared with nonusers, despite the two groups currently no longer exhibiting significantly different levels of circulating estradiol. After an 8-year hiatus in treatment, HT provides limited advantages in gastrocnemius medialis muscle properties. Interestingly, it perhaps enhances vitality despite prolonged cessation, which in the longer term would facilitate greater physical independence, especially considering the association of sedentary behavior with greater frailty.

Effects of N-Acetyl-Carnosine Treatment on Aging and Carbonyl Stress

By 2050 the number of individuals over the age of 80y will triple to reach 426 million and the rate of age-related comorbidities has also increased precipitously as our global population has continued to age. Currently, there is no clinically approved treatment for age-related functional decline creating demand for the development of such treatments. Our lab previously demonstrated that carbonyl stress is exacerbated in muscles during a hindlimb unloading (HU) model of inactivity. Importantly, the accumulation of proteins modified by the reactive lipid carbonyl 4HNE, as well as muscle dysfunction and atrophy, were attenuated in HU mice treated with the carbonyl-scavenging dipeptide N-acetyl-carnosine (N-Ac-Carn). Therefore, we hypothesized that N-Ac-Carn could prevent carbonyl stress in aging muscles and other tissues. 17-month-old male and female C57Bl6J mice from the NIA colony were treated for 6-months with 80 mM N-Ac-Carn or normal (CON) water. Before and after the 6-month intervention we assessed several markers of health including glucose tolerance, kidney, muscle, bone, and cognitive function. N-Ac-Carn preserved ex vivo muscle force production in soleus ( p=0.0015) and EDL ( p=0.0008) muscles from female but not male mice. N-Ac-Carn treated mice also possessed superior bone volume compared to CON ( p=0.0046). Following terminal tissue collection, we also assessed muscles for carbonyl stress by probing for proteins modified by total carbonyls, 4HNE, MDA, and methylglyoxal. N-Ac-Carn did not attenuate 4HNE, MDA, or total carbonyls in gastrocnemius. However, N-Ac-Carn showed strong trends for attenuating 4HNE burden in both soleus and EDL muscles. N-Ac-Carn is an endogenously produced dipeptide that is safe for human consumption and affordable making it a promising therapeutic strategy for the mitigation of age-related functional decline. AG074535-02S2. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sexual dimorphism in renal metabolism, hemodynamics and diseases

Age-related decline of renal function is faster in males than in age-matched females, manifesting in increased susceptibility to both chronic and acute kidney diseases among males. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments, where most reabsorption of water and salt happens, with a high energetic demand. Recent work suggests that male PTs undergo excessive oxidative stress to meet the high energetic demand, while female PTs exhibit an anti-oxidation state. However, it remains elusive how the observed molecular differences relate to sex disparities in renal physiology and pathophysiology. Glomerular filtration rate (GFR) is tightly regulated by tubuloglomerular feedback (TGF) within renal tubules to optimize ultrafiltration of plasma and reabsorption of essential molecules. Importantly, GFR shows a sustained oscillatory pattern over time in rodents, and loss of GFR oscillations is associated with cessation of reabsorption activities and with the occurrence of ischemia-reperfusion injuries in the kidney, as well as with systemic hypertension. To study the relationship between intracellular metabolic events and renal physiology, we developed a mathematical model of TGF linking metabolic regulation within PT cells to fluid handling and salt reabsorption in the nephron, using renal blood flow and intra-vital imaging data. Analysis of this model revealed that dynamical properties of the system differ between male and female kidneys, resulting in male kidneys being more prone to stress-induced damage, thus building towards an explanation for sexual dimorphism in renal aging and diseases. With this mechanistic model, our work also provides insight into how pharmacological interventions can be employed to confer renoprotection. The authors received no funding for this study. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Correlation between serum vitamin D levels and bone mass density evaluated by radiofrequency echographic multi-spectrometry technology (REMS) in menopausal women.

Osteoporosis is a common condition associated with an increased risk of bone fractures due to fragility. Bone mineral density (BMD) is lower in menopausal women due to estrogen deficiency, age-related decline in osteoblast function, decreased calcium absorption, and reduced synthesis of vitamin D, which lead to osteoporosis. The aim of this study was to determine the correlation between serum vitamin D levels and BMD assessed using radiofrequency echographic multi-spectrometry technology (REMS) in menopausal women. A cross-sectional study was conducted at Prof. Dr. Chairuddin P. Lubis Hospital of Universitas Sumatera Utara, Medan, Indonesia, from May 2023 to August 2023. Consecutive sampling method was employed to sample menopausal women with no history of hysterectomy or oophorectomy (unilateral or bilateral), and no history of hormone replacement therapy or vitamin D supplementation. Interviews and physical examinations were conducted to obtain the characteristics of the subjects (age, duration of menopause, and body mass index). The 25(OH)D level was measured using immunoassay and REMS examination was conducted to assess BMD. The Spearman correlation test was used to assess the correlation between serum vitamin D levels and BMD. A total of 32 menopausal women were included in this study with the average vitamin D level was 18.05±5.81 ng/mL, and the mean BMD level was -2.13±1.23. The data showed a significant positive correlation between serum vitamin D levels and BMD in menopausal women (r=0.710; p=0.020). This study highlights that REMS could be useful as an alternative to dual-energy x-ray absorptiometry (DXA) to assess DMD in postmenopausal women.

Neuronal microstructural changes in the human brain are associated with neurocognitive aging.

Gray matter (GM) alterations play a role in aging-related disorders like Alzheimer's disease and related dementias, yet MRI studies mainly focus on macroscopic changes. Although reliable indicators of atrophy, morphological metrics like cortical thickness lack the sensitivity to detect early changes preceding visible atrophy. Our study aimed at exploring the potential of diffusion MRI in unveiling sensitive markers of cortical and subcortical age-related microstructural changes and assessing their associations with cognitive and behavioral deficits. We leveraged the Human Connectome Project-Aging cohort that included 707 participants (394 female; median age = 58, range = 36-90 years) and applied the powerful mean apparent diffusion propagator model to measure microstructural parameters, along with comprehensive behavioral and cognitive test scores. Both macro- and microstructural GM characteristics were strongly associated with age, with widespread significant microstructural correlations reflective of cellular morphological changes, reduced cellular density, increased extracellular volume, and increased membrane permeability. Importantly, when correlating MRI and cognitive test scores, our findings revealed no link between macrostructural volumetric changes and neurobehavioral performance. However, we found that cellular and extracellular alterations in cortical and subcortical GM regions were associated with neurobehavioral performance. Based on these findings, it is hypothesized that increased microstructural heterogeneity and decreased neurite orientation dispersion precede macrostructural changes, and that they play an important role in subsequent cognitive decline. These alterations are suggested to be early markers of neurocognitive performance that may distinctly aid in identifying the mechanisms underlying phenotypic aging and subsequent age-related functional decline.

Effectiveness of multi-modal home-based videoconference interventions on sleep in older adults: study protocol for a randomized controlled trial.

Aging is characterized by substantial changes in sleep architecture that negatively impact fitness, quality of life, mood, and cognitive functioning. Older adults often fail to reach the recommended level of physical activity to prevent the age-related decline in sleep function, partly because of geographical barriers. Implementing home-based interventions could surmount these obstacles, thereby encouraging older adults to stay active, with videoconference administration emerging as a promising solution. Increasing the availability of biological rhythms synchronizers, such as physical activity, light exposure, or vestibular stimulation, represents a viable non-pharmacological strategy for entraining circadian rhythms and potentially fortifying the sleep-wake cycle, thereby enhancing sleep in aging. This study aims to (1) assess the impact of remote physical exercise training and its combination with bright light exposure, and (2) investigate the specific contribution of galvanic vestibular stimulation, to sleep quality among healthy older adults with sleep complaints. One hundred healthy older adults aged 60-70 years with sleep complaints will be randomly allocated to one of four groups: a physical exercise training group (n = 25), a physical exercise training combined with bright light exposure group (n = 25), a galvanic vestibular stimulation group (n = 25) or a control group (i.e., health education) (n = 25). While physical exercise training and health education will be supervised via videoconference at home, bright light exposure (for the physical exercise training combined with bright light exposure group) and vestibular stimulation will be self-administered at home. Pre-and post-tests will be conducted to evaluate various parameters, including sleep (polysomnography, subjective questionnaires), circadian rhythms (actigraphy, temperature), fitness (physical: VO2 peak, muscular function; and motor: balance, and functional mobility), cognition (executive function, long-term memory), quality of life and mood (anxiety and depression). The findings will be anticipated to inform the development of recommendations and non-pharmaceutical preventive strategies for enhancing sleep quality in older adults, potentially leading to improvements in fitness, cognition, quality of life, and mood throughout aging.

Aging-related defects in macrophage function are driven by MYC and USF1 transcriptional programs

Macrophages are central innate immune cells whose function declines with age. The molecular mechanisms underlying age-related changes remain poorly understood, particularly in human macrophages. We report a substantial reduction in phagocytosis, migration, and chemotaxis in human monocyte-derived macrophages (MDMs) from older (>50 years old) compared with younger (18-30 years old) donors, alongside downregulation of transcription factors MYC and USF1. In MDMs from young donors, knockdown of MYC or USF1 decreases phagocytosis and chemotaxis and alters the expression of associated genes, alongside adhesion and extracellular matrix remodeling. A concordant dysregulation of MYC and USF1 target genes is also seen in MDMs from older donors. Furthermore, older age and loss of either MYC or USF1 in MDMs leads to an increased cell size, altered morphology, and reduced actin content. Together, these results define MYC and USF1 as key drivers of MDM age-related functional decline and identify downstream targets to improve macrophage function in aging.

Enhancing Oocyte Quality in Aging Mice: Insights from Mesenchymal Stem Cell Therapy and FOXO3a Signaling Pathway Activation.

Ovarian aging reduced the quality of oocytes, resulting in age-related female infertility. It is reported that mesenchymal stem cells (MSCs) therapy can improve age-related ovarian function decline and the success rate of in vitro maturation (IVM) in assisted reproductive therapy. In order to investigate the effectiveness and mechanisms of MSCs to enhance oocyte quality of cumulus oocyte complexes (COCs) in advanced age, this study focus on the respective functional improvement of oocytes and granulosa cells (GCs) from aging mice and further to explore and verify the possible mechanisms. Here, we studied a popular but significant protein of follicular development, Forkhead box O-3a (FOXO3a), which is a transcription factor that mediates a variety of cellular processes, but the functions of which in regulating oocyte quality in MSCs therapy still remain inconclusive. In this study, the RNA-seq data of metaphase II (MII) oocytes and GCs isolated from COCs confirmed that, GCs of immature follicles show the most potential to be the targeted cells of bone marrow mesenchymal stem cells (BMSCs) by FOXO3a signaling pathway. Furthermore, we demonstrated the effectiveness of BMSCs co-culture with aging COCs to enhance oocyte quality and found its mechanism to function via ameliorating the biological function of GCs by alleviating FOXO3a levels. These results provide significant fundamental research on MSCs therapy on ovarian aging, as well as offering guidance for raising the success rate of assisted reproductive technology such IVM in clinical and non-clinical settings.

Establishing healthy longevity clinics in publicly funded hospitals.

Healthy longevity medicine integrates geroscience and other disciplines into clinical settings, aiming to optimize health throughout one's lifespan. Multiple factors have led to increased consumer engagement, with private clinics currently meeting the demand for guidance to improve healthy longevity. The establishment of healthy longevity clinics in publicly funded hospitals is a significant development, making longevity-focused healthcare more accessible. These clinics rely on multidisciplinary teams of physicians and allied health professionals. Diagnostics involve comprehensive evaluations of medical history, physical examinations, and various clinical tests to detect early signs of age-related functional decline. Interventions in healthy longevity medicine encompass lifestyle modifications, supplements, repurposed drugs, and social and environmental interventions. Collaboration with research institutions and industry partners is crucial for advancing healthy longevity medicine and creating standardized protocols. In this article, we review the process of creating healthy longevity clinics in public hospitals toensure the best possible care for individuals pursuing healthy longevity.

Sarcopenia as the Mobility Phenotype of Aging: Clinical Implications.

Sarcopenia, which is characterized by an age-related decline in muscle mass and function, poses significant challenges to geriatric care. Its definition has evolved from muscle-specific criteria to include muscle mass, muscle function, and physical performance, recognizing sarcopenia as a physical frailty. Sarcopenia is associated with adverse outcomes, including mortality, falls, fractures, cognitive decline, and admission to long-term care facilities. Neuromechanical factors, protein-energy balance, and muscle protein synthesis-breakdown mechanisms contribute to its pathophysiology. The identification of sarcopenia involves screening tests and a comprehensive assessment of muscle mass, strength, and physical function. Clinical approaches aligned with the principles of comprehensive geriatric assessment prioritize patient-centered care. This assessment aids in identifying issues related to activities of daily living, cognition, mood, nutrition, and social support, alongside other aspects. The general approach to factors underlying muscle loss and functional decline in patients with sarcopenia includes managing chronic diseases and evaluating administered medications, with interventions including exercise and nutrition, as well as evolving pharmacological options. Ongoing research targeting pathways, such as myostatin-activin and exercise mimetics, holds promise for pharmacological interventions. In summary, sarcopenia requires a multifaceted approach, acknowledging its complex etiology and tailoring interventions to individual patient needs.

Effects of Alterations in Acid-Base Effects on Insulin Signaling.

Insulin tightly regulates glucose levels within a narrow range through its action on muscle, adipose tissue and the liver. The activation of insulin receptors activates multiple intracellular pathways with different functions. Another tightly regulated complex system in the body is acid-base balance. Metabolic acidosis, defined as a blood pH < 7.35 and serum bicarbonate < 22 mmol/L, has clear pathophysiologic consequences including an effect on insulin action. With the ongoing intake of typical acid-producing Western diets and the age-related decline in renal function, there is an increase in acid levels within the range considered to be normal. This modest increase in acidosis is referred to as "acid stress" and it may have some pathophysiological consequences. In this article, we discuss the effects of acid stress on insulin actions in different tissues.

Why do we age? The main signs of aging

Aging is a gradual and irreversible pathophysiological process. This is manifested in the decline of tissue and cell functions and a significant variety of pathologies associated with aging, including neurodegenerative diseases, cardiovascular diseases, metabolic disorders, increased risk of diseases of the skeleton and the immune system. Although modern medical advances have made a certain contribution to human health and greatly extended life expectancy, along with the aging of society, various chronic diseases are gradually emerging, which are the most important causes of disability and death of the elderly. Aim. The aim of the work is to analyze modern ideas in the field of causes and manifestations of aging processes for the possibility of developing a strategy to slow down its course. At the molecular and cellular level, aging is a complex biological process involving the gradual deterioration of various cellular and molecular processes in the body over time. The length of a person’s life is closely related to the decrease in the possibilities of repair and regeneration of tissues and organs. In response to stress at the molecular, cellular, and systemic levels, genetic, epigenetic, and environmental regulatory factors cause a decrease in the body’s physiological capabilities. They use complex molecular mechanisms that together contribute to aging. Molecular mechanisms (such as telomere shortening, accumulation of DNA damage, metabolic changes, and excessive free radical generation) strongly link various factors to the rate of aging. Collectively, these mechanisms inhibit cell proliferation, alter metabolism and gene expression, and induce high levels of free radicals, maintaining a senescent cell phenotype. Although the number of early senescent cells is low, they can limit the regenerative capacity of tissue stem cells and lead to the accumulation of cellular damage, thereby contributing to age-related diseases. Conclusions. Current advances in high-throughput genomics, transcriptomics, proteomics, and metabolomics enable the characterization and quantification of thousands of epigenetic markers, transcripts, proteins, metabolites, and can reveal general changes that occur with age in complex organisms at the molecular level. Thus, the integration of these molecular markers and related molecular mechanisms into a comprehensive assessment of biological age to prevent age-related functional decline and morbidity is becoming an increasingly pressing issue in medical science and should be implemented in practice as soon as possible.

Exercise Alleviates Aging of Adipose Tissue through Adipokine Regulation.

Adipose tissue undergoes changes with aging, leading to increased adiposity, inflammatory cell infiltration, reduced angiogenesis, heightened oxidative stress, and alterations in its metabolic function. Regular exercise has been recognized as a powerful intervention that can positively influence adipose tissue health and mitigate the effects of aging. However, the molecular mechanisms underlying the benefits of regular exercise on aging adipose tissue function remain poorly understood. Adipokines released through regular exercise play a potential role in mitigating adipose tissue aging, enhancing the metabolism of glucose and lipids, reducing inflammation and fibrosis, and promoting fat browning and thermogenesis. This review comprehensively summarizes the benefits of regular exercise in addressing the age-related decline in adipose tissue function. Utilizing relevant examples of this approach, we address the possibility of designing therapeutic interventions based on these molecular mechanisms.

Inhibition of miR-143-3p Restores Blood-Testis Barrier Function and Ameliorates Sertoli Cell Senescence.

Due to the increasing trend of delayed childbirth, the age-related decline in male reproductive function has become a widely recognized issue. Sertoli cells (SCs) play a vital role in creating the necessary microenvironment for spermatogenesis in the testis. However, the mechanism underlying Sertoli cell aging is still unclear. In this study, senescent Sertoli cells showed a substantial upregulation of miR-143-3p expression. miR-143-3p was found to limit Sertoli cell proliferation, promote cellular senescence, and cause blood-testis barrier (BTB) dysfunction by targeting ubiquitin-conjugating enzyme E2 E3 (UBE2E3). Additionally, the TGF-β receptor inhibitor SB431542 showed potential in alleviating age-related BTB dysfunction, rescuing testicular atrophy, and reversing the reduction in germ cell numbers by negatively regulating miR-143-3p. These findings clarified the regulatory pathways underlying Sertoli cell senescence and suggested a promising therapeutic approach to restore BTB function, alleviate Sertoli cell senescence, and improve reproductive outcomes for individuals facing fertility challenges.

Unlocking the dark matter: noncoding RNAs and RNA modifications in cardiac aging.

Cardiac aging is a multifaceted process that encompasses structural and functional alterations culminating in heart failure. As the elderly population continues to expand, there is a growing urgent need for interventions to combat age-related cardiac functional decline. Noncoding RNAs have emerged as critical regulators of cellular and biochemical processes underlying cardiac disease. This review summarizes our current understanding of how noncoding RNAs function in the heart during aging, with particular emphasis on mechanisms of RNA modification that control their activity. Targeting noncoding RNAs as potential novel therapeutics in cardiac aging is also discussed.

Dietary Intervention Favorably Influences Physical Functioning: The Women’s Health Initiative Randomized Dietary Modification Trial

BackgroundIn the Women’s Health Initiative Dietary Modification randomized trial, the dietary intervention reduced breast cancer mortality by 21% (P = .02) and increased physical activity as well. ObjectiveTherefore, the aim was to examine whether or not these lifestyle changes attenuated age-related physical functioning decline. DesignIn a randomized trial, the influence of 8 years of a low-fat dietary pattern intervention was examined through 20 years of cumulative follow-up. Participants and settingFrom 1993 to 1998, 48,835 postmenopausal women, ages 50 to 79 years with no prior breast cancer and negative baseline mammogram were randomized at 40 US clinical centers to dietary intervention or usual diet comparison groups (40 out of 60). The intervention significantly reduced fat intake and increased vegetable, fruit, and grain intake. Main outcome measuresIn post hoc analyses, physical functioning, assessed using the RAND 36-Item Short Form Health Survey, evaluated quality or limitations of 10 hierarchical physical activities. Longitudinal physical functioning, reported against a disability threshold (when assistance in daily activities is required) was the primary study outcome. Statistical analyses performedSemiparametric linear mixed effect models were used to contrast physical functioning trajectories by randomization groups. ResultsPhysical functioning score, assessed 495,317 times with 11.0 (median) assessments per participant, was significantly higher in the intervention vs comparison groups through 12 years of cumulative follow-up (P = .001), representing a reduction in age-related functional decline. The intervention effect subsequently attenuated and did not delay time to the disability threshold. Among women in the dietary intervention vs comparison groups, aged 50 to 59 years, who were physically inactive at entry, a persistent, statistically significant, favorable influence on physical functioning with associated delay in crossing the disability threshold by approximately a year was seen (P value for interaction = .007). ConclusionsIn the Women’s Health Initiative Dietary Modification randomized trial, a dietary intervention that significantly reduced breast cancer mortality also significantly reduced age-related functional decline through 12 years, which was attenuated with longer follow-up.