Age-related Functional Decline Research Articles

Elastin haploinsufficiency accelerates age-related structural and functional changes in the renal microvasculature and impairment of renal hemodynamics in female mice.

Age-related decline in functional elastin is associated with increased arterial stiffness, a known risk factor for developing cardiovascular disease. While the contribution of elastin insufficiency to the stiffening of conduit arteries is well described, little is known about the impact on the structure and function of the resistance vasculature, which contributes to total peripheral resistance and the regulation of organ perfusion. In this study, we determined how elastin insufficiency impinges on age-related changes in the structure and biomechanical properties of the renal microvasculature, altering renal hemodynamics and the response of the renal vascular bed to changes in renal perfusion pressure (RPP) in female mice. Using Doppler ultrasonography, we found that resistive index and pulsatility index were elevated in young Eln +/- and aged mice. Histological examination showed thinner internal and external elastic laminae, accompanied by increased elastin fragmentation in the medial layer without any calcium deposits in the small intrarenal arteries of kidneys from young Eln +/- and aged mice. Pressure myography of interlobar arteries showed that vessels from young Eln +/- and aged mice had a slight decrease in distensibility during pressure loading but a substantial decline in vascular recoil efficiency upon pressure unloading. To examine whether structural changes in the renal microvasculature influenced renal hemodynamics, we clamped neurohumoral input and increased renal perfusion pressure by simultaneously occluding the superior mesenteric and celiac arteries. Increased renal perfusion pressure caused robust changes in blood pressure in all groups; however, changes in renal vascular resistance and renal blood flow (RBF) were blunted in young Eln +/- and aged mice, accompanied by decreased autoregulatory index, indicating greater impairment of renal autoregulation. Finally, increased pulse pressure in aged Eln +/- mice positively correlated with high renal blood flow. Together, our data show that the loss of elastin negatively affects the structural and functional integrity of the renal microvasculature, ultimately worsening age-related decline in kidney function.

Senescent CD8+ T cells acquire NK cell-like innate functions to promote antitumor immunity.

It has been suggested that aging of the immune system (immunosenescence) results in a decline in the acquired immune response, which is associated with an increase in age-related tumorigenesis. T-cell senescence plays a critical role in immunosenescence and is involved in the age-related decline of the immune function, which increases susceptibility to certain cancers. However, it has been shown that CD8+ T cells with the senescent T-cell phenotype acquire an natural killer (NK) cell-like function and are involved in tumor elimination. Therefore, the role of senescent CD8+ T cells in tumor immunity remains to be elucidated. In this study, we investigated the role of senescent CD8+ T cells in tumor immunity. In a murine model of transferred with B16 melanoma, lung metastasis was significantly suppressed in aged mice (age ≥30 weeks) in comparison to young mice (age 6-10 weeks). We evaluated the cytotoxic activity of CD8+ T cells in vitro and found that CD8+ T cells from aged mice activated in vitro exhibited increased cytotoxic activity in comparison to those from young mice. We used Menin-deficient effector T cells as a model for senescent CD8+ T cells and found that cytotoxic activity and the expression of NK receptors were upregulated in Menin-deficient senescent CD8+ T cells. Furthermore, Menin-deficient CD8+ T cells can eliminate tumor cells in an antigen-independent manner. These results suggest that senescent effector CD8+ T cells may contribute to tumor immunity in the elderly by acquiring NK-like innate immune functions, such as antigen-independent cytotoxic activity.

Classical Ballet for Women Aged Over 50 Years: Investigating Balance, Strength, and Range of Motion

ABSTRACT Background: Regular exercise can mitigate the loss of strength, balance, and flexibility that contribute to age-related decline in physical function and mobility. However, traditional exercise interventions often report poor adherence rates. There is growing interest in classical ballet as an enjoyable exercise modality for adults in middle to late age. Classical ballet requires muscular strength, coordination, and flexibility. The current study investigated a classical ballet intervention on the balance, physical function, and range of motion of women aged over 50 years. Methods: Twenty-two healthy female participants (aged 56.2 (4.5) years (mean (SD)) completed a 10-week ballet intervention. Results: This single-arm study showed significant improvements (p<.05) in lower limb strength (measured by 5 times sit-to-stand and forward leap) and high adherence rates (95% adherence for participants who completed the intervention). No adverse events were reported. Improvements in balance were reported in the left leg only (as measured by center of pressure ellipse area in the parallel retiré condition). Conclusions: These results allude to the positive effects of ballet training on strength and balance in adults aged 50 years and over. High adherence rates suggest that ballet training was enjoyed and may thus be a long-term exercise modality for this population. Although this study was a single-arm design, it suggests promising results for future research wishing to evaluate the effectiveness of classical ballet training using randomized controlled trial designs.

Geroprotective Effect of Levilactobacillus brevis and Weizmannia coagulans in Caenorhabditis elegans.

The prophylactic use of lactic acid bacteria (LAB) to maintain human health is one of the most important research areas in recent times. LAB supplementation confers a wide range of health benefits to the host, but few studies have focused on their possible role in delaying the aging process. This study explored the health and life-promoting properties of two LAB, Levilactobacillus brevis and Weizmannia coagulans, using the Caenorhabditis elegans model. We found that L. brevis and W. coagulans enhanced the intestinal integrity and intestinal barrier functions without affecting the overall physiological functions of C. elegans. Wild-type worms preconditioned with LAB strains increased their survival under oxidative and thermal stress conditions by reducing intracellular reactive oxygen levels. Live L. brevis and W. coagulans significantly extended the lifespan of C. elegans under standard laboratory conditions independently of dietary restrictions. Genetic and reporter gene expression analysis revealed that L. brevis and W. coagulans extend lifespan via insulin/insulin-like growth factor-1 signaling and the p38 MAPK signaling axis. Furthermore, sirtuin, JNK MAPK, and mitochondrial respiratory complexes were found to be partially involved in W. coagulans-mediated lifespan extension and stress resilience. Preconditioning with LAB ameliorated age-related functional decline in C. elegans and reduced ectopic fat deposition in an NHR-49-dependent manner. Together, our findings indicated that L. brevis and W. coagulans are worth exploring further as "gerobiotic" candidates to delay aging and improve the healthspan of the host.

Self-Reported Questionnaire to Evaluate Functional Abilities in Middle Age: A Call for Delphi Expert Panel

Early detection of functional decline is important for promoting optimal aging. Self-reported questionnaires can efficiently assess functional abilities. Therefore, we aimed to highlight the lack of functional ability assessment questionnaires for the middle-aged population (MA, 45-65 years) and the need to develop such a questionnaire. An online search was performed to find questionnaires quantifying self-reported performance and functional abilities at MA. We also conducted an online survey of a group of the MA population and interviewed individuals who reported age-related functional decline. Eight potentially relevant questionnaires were found, and one hundred and twenty-three individuals responded to our survey, five of whom were interviewed. None of the questionnaires were specifically designed to assess functional capacity at MA, and most of the questionnaires are likely to have a ceiling effect in assessing the MA population. Furthermore, the questionnaires do not capture functions related to dynamic balance, flexibility, and maximum strength, which are reported as difficult by our respondents, making them less appropriate for assessing function at MA. There is a need to engage a Delphi expert panel of several relevant healthcare professionals to develop a functional capacity assessment questionnaire for MA.

RAGE is a critical factor of sex-based differences in age-induced kidney damage.

Introduction: Advanced glycation end products (AGEs) are a heterogeneous group of molecules with potential pathophysiological effects on the kidneys. Fibrosis together with the accumulation of AGEs has been investigated for its contribution to age-related decline in renal function. AGEs mediate their effects in large parts through their interactions with the receptor for AGEs (RAGE). RAGE is a transmembrane protein that belongs to the immunoglobulin superfamily and has the ability to interact with multiple pro-inflammatory/pro-oxidative ligands. The role of RAGE in aging kidneys has not been fully characterized, especially for sex-based differences. Methods: Therefore, we analyzed constitutive RAGE knockout (KO) mice in an age- and sex-dependent manner. Paraffin-embedded kidney sections were used for histological analysis and protein expression of fibrosis and damage markers. RNA expression analysis from the kidney cortex was done by qPCR for AGE receptors, kidney damage, and early inflammation/fibrosis factors. FACS analysis was used for immune cell profiling of the kidneys. Results: Histological analysis revealed enhanced infiltration of immune cells (positive for B220) in aged (>70weeks old) KO mice in both sexes. FACS analysis revealed a similar pattern of enhanced B-1a cells in aged KO mice. There was an age-based increase in pro-fibrotic and pro-inflammatory markers (IL-6, TNF, TGF-β1, and SNAIL1) in KO male mice that presumably contributed to renal fibrosis and renal damage (glomerular and tubular). In fact, in KO mice, there was an age-dependent increase in renal damage (assessed by NGAL and KIM1) that was accompanied by increased fibrosis (assessed by CTGF). This effect was more pronounced in male KO mice than in the female KO mice. In contrast to the KO animals, no significant increase in damage markers was detectable in wild-type animals at the age examined (>70weeks old). Moreover, there is an age-based increase in AGEs and scavenger receptor MSR-A2 in the kidneys. Discussion: Our data suggest that the loss of the clearance receptor RAGE in male animals further accelerates age-dependent renal damage; this could be in part due to an increase in AGEs load during aging and the absence of protective female hormones. By contrast, in females, RAGE expression seems to play only a minor role when compared to tissue pathology.

Coenzyme Q10 supplementation improves the motor function of middle-aged mice by restoring the neuronal activity of the motor cortex

Physiological aging causes motor function decline and anatomical and biochemical changes in the motor cortex. We confirmed that middle-aged mice at 15–18 months old show motor function decline, which can be restored to the young adult level by supplementing with mitochondrial electron transporter coenzyme Q10 (CoQ10) as a water-soluble nanoformula by drinking water for 1 week. CoQ10 supplementation concurrently improved brain mitochondrial respiration but not muscle strength. Notably, we identified an age-related decline in field excitatory postsynaptic potential (fEPSP) amplitude in the pathway from layers II/III to V of the primary motor area of middle-aged mice, which was restored to the young adult level by supplementing with CoQ10 for 1 week but not by administering CoQ10 acutely to brain slices. Interestingly, CoQ10 with high-frequency stimulation induced NMDA receptor-dependent long-term potentiation (LTP) in layer V of the primary motor cortex of middle-aged mice. Importantly, the fEPSP amplitude showed a larger input‒output relationship after CoQ10-dependent LTP expression. These data suggest that CoQ10 restores the motor function of middle-aged mice by improving brain mitochondrial function and the basal fEPSP level of the motor cortex, potentially by enhancing synaptic plasticity efficacy. Thus, CoQ10 supplementation may ameliorate the age-related decline in motor function in humans.

'Food for thought' in devising aging-simulation experience.

Aging simulation (experiencing age-related functional decline), an educational tool commonly used in geriatrics education, is widely recognised for being able to drive positive attitudinal change toward older patient care. However, scholars1 warned that, given its focus on age-related limitations and disabilities, the method may lead junior medical students to take age-related barriers as impending and irrevocable, thereby reinforcing myths and negative assumptions on ‘growing old’. Prior research reported that, in aging simulation, interest in geriatric care (driven by empathy) might be achieved at the expense of worsening self-views on personal aging. To mitigate this unintended-side effect, a recommendation made was to integrate learning strategies of ‘demystifying myths’ and ‘experiencing aging’. Dysphagia is a health condition common in old age and often associated with malnutrition, pneumonia and dehydration. It can also be part of normal aging, given how the aetiologies also grow with age. Internationally, prevalence of dysphagia in aged care facilities has been estimated to be up to 40%. Yet, awareness and recognition of its impacts on one's lived experience are lacking among medical officers. While other age-related physiological changes such as walking difficulties, visual and hearing impairments are often covered in traditional aging simulation, dysphagia remains an unaddressed topic. In collaboration with a Hong Kong-based social enterpirse “The Project Futurus”, we piloted a 2.5-hour aging simulation workshop centred around dysphagia in old age. At a teaching kitchen, second-year MBBS students could personally relate to the mealtime experience of dysphagic older persons. The activity was part of a Medical Humanities Curriculum at HKU. Quota was capped at 20 owing to COVID restrictions. Instead of a focus on age-related difficulties and feelings of frustrations that usually characterize traditional aging simulation, our workshop, titled ‘Dignified meal and sparks for life’, exposes students to the realities of aging while shedding a positive light on wellbeing in old age: Before class, students were invited to experience food similar to porridge being served to dysphagic patients in the past. In class, students received (i) a mini-lecture demystifying dysphagia diet, and (ii) a live demonstration on using Japanese Engay (easy-to-swallow) cooking techniques to create more uplifting dysphagia diet with aesthetic appeal and texture. Then, students (iii) worked in groups to prepare and mould texture-modified meals, followed by (iv) tasting and debriefing on how the lived experience of dysphagic older persons could be transformed through person-centred care. We administered the validated UCLA Geriatrics Attitudes Scale (UCLA-GAS) to assess student attitudes toward older patient care, and Reactions to Ageing Questionnaire (RAQ) to assess attitudes toward personal aging. All participants (n = 20) completed pre- and post-questionnaires. Mean age was 19.5. Contrary to an earlier study,1 our workshop had improved attitudes toward geriatric patient care (p = 0.02) and personal aging (p = 0.042) in second-year undergraduate medical students. Cohen's d was 0.492 and 0.406, respectively, indicating moderate effect size in both measures. Despite a small sample, we have developed a new form of aging simulation pertaining to the human experience of dysphagia in old age. By integrating elements of ‘demystifying myths’ and re-orienting the activity's focal point from age-related difficulties to enablers of wellbeing, our pilot throws light on how aging simulation's unintended negative side-effect could be avoided.

Safer cycling in older age (SiFAr): effects of a multi-component cycle training. a randomized controlled trial

BackgroundThe risk of older adults being injured or killed in a bicycle accident increases significantly due to the age-related decline of physical function. Therefore, targeted interventions for older adults to improve safe cycling competence (CC) are urgently needed.MethodsThe “Safer Cycling in Older Age” (SiFAr) randomized controlled trial investigated if a progressive multi-component training program related to cycling improves CC of older adults. Between June 2020 and May 2022, 127 community-dwelling persons living in the area Nürnberg-Fürth-Erlangen, Germany aged 65 years and older were recruited, who are either (1) beginners with the e-bike or (2) feeling self-reported unsteadiness when cycling or (3) uptaking cycling after a longer break. Participants were either randomized 1:1 to an intervention group (IG; cycling exercise program, 8 sessions within 3 months) or an active control group (aCG; health recommendations). The CC as primary outcome was tested not blinded in a standardized cycle course prior and after the intervention period and after 6–9 months, which consists of variant tasks requiring skills related to daily traffic situations. Regression analyses with difference of errors in the cycling course as dependent variable and group as independent variable adjusted for covariates (gender, number of errors at baseline, bicycle type, age and cycled distance) were performed.Results96 participants (73.4 ± 5.1 years; 59.4% female) were analyzed for primary outcome. Compared to the aCG (n = 49), the IG (n = 47) made an average of 2.37 fewer errors in the cycle course after the 3 months intervention period (p = 0.004). People with more errors at baseline had higher potential for improvement (B=-0.38; p < 0.001). Women on average made 2.31 (p = 0.016) more errors than men, even after intervention. All other confounders had no significant effect on the difference in errors. The intervention effect was very stable until 6–9 months after the intervention (B=-3.07, p = 0.003), but decreased with a higher age at baseline in the adjusted model (B = 0.21, p = 0.0499).ConclusionThe SiFAr program increases cycling skills among older adults with self-perceived needs for improvement in CC and could easily be made available to a broad public due to its standardized structure and a train-the-trainer approach.Trial RegistrationThis study was registered with clinicaltrials.gov: NCT04362514 (27/04/2020), https://clinicaltrials.gov/ct2/show/NCT04362514.

The wrinkles of the soul- a psychoneuroimmunological approach to aging

IntroductionPsychoneuroimmunology is a discipline that has emerged over the past decades as a broad interdisciplinary field that closely observes the relationship between the psychological state, the nervous system, the endocrine system, and the immune system. The natural aging process leads to alterations in the immune functions, involving lymphocyte dysregulation, and therefore leading to a higher risk of developing coronary artery diseases, infectious diseases or even cancer.ObjectivesThe aim of our inquiry is to evaluate the existing body of work with a focus on studies that observed the intricate connections between psychosocial factors and immunity.MethodsWe performed a systematic review on PubMed and a targeted literature search concentrating on all the factors involved in immunosenescence and their consequences.ResultsThe causality between emotional stressors (acute or chronic), lack of social support, adverse life events, coping mechanisms, personality traits, as well as endocrine changes and multiple age-related pathologies is often undeniable. Other relevant factors include nutrition, sleep, physical activity and substance use. As people grow older, they face a number of psychosocial stressors, such as retirement, social isolation, loss of independence, low income, a decrease in productivity and also somatic comorbidities. These factors, together with an age-related decline in immune function, can constitute not only a psychosocial disadvantage of the elderly, but also a risk factor able to trigger further deterioration of the immune system.ConclusionsAge-associated alterations of the immune response represent a complex concept. Given that we are dealing with the phenomenon of aging in the general population, the field of psychoneuroimmunology can make a significant contribution in establishing the different mechanisms through which seniors can cushion the impact of stressors in regards to health and illness. Therefore, we can pave the way for an individualized approach and support for patients, as well as provide better therapeutic outcomes.Disclosure of InterestNone Declared

Molecular and Functional Changes to Postsynaptic Cholinergic Signaling in the Vestibular Sensory Organs of Aging C57BL/6Mice.

Cholinergic circuits in the central nervous system are vulnerable to age-related functional decline, but it is not known if aging impacts cholinergic signaling in the vestibular sensory organs, which are critically important to balance maintenance and visual gaze stability. We have previously shown cholinergic neurotransmission between vestibular efferent terminals and type II mechanosensory hair cells requires the alpha9 (Chrna9) nicotinic receptor subunit. Homozygous knockout of the alpha9 subunit causes vestibulo-ocular reflex adaptation deficits that mirror those observed in aged mice. This prompted examination of cholinergic signaling in the vestibular sensory organs of aged mice. We confirmed older (>24months) mice had impaired performance in a balance beam task compared to young (3-4months) adult mice. While there was no qualitative loss of cholinergic axon varicosities in the crista ampullaris of old mice, qPCR analysis revealed reduced expression of nicotinic receptor subunit genes Chrna1, Chrna9, and Chrna10 in the cristae of old relative to young mice. Functionally, single-cell patch clamp recordings taken from type II vestibular hair cells exposed to acetylcholine show reduced conductance through alpha9/10 subunit-containing nicotinic receptors in older mice, despite preserved passive membrane properties and voltage-activated conductances. These findings suggest that cholinergic signaling in the peripheral vestibular sensory organs is vulnerable to aging processes, manifesting in dynamic molecular and functional age-related changes. Given the importance of these organs to our everyday activities, and the dramatic increase in fall incidence in the older, further investigation into the mechanisms of altered peripheral vestibular function in older humans is warranted.

Dysregulated proteostasis network in neuronal diseases.

Long-term maintenance of synaptic connections is important for brain function, which depends on varying proteostatic regulations to govern the functional integrity of neuronal proteomes. Proteostasis supports an interconnection of pathways that regulates the fate of proteins from synthesis to degradation. Defects in proteostatic signaling are associated with age-related functional decline and neurodegenerative diseases. Recent studies have advanced our knowledge of how cells have evolved distinct mechanisms to safely control protein homeostasis during synthesis, folding and degradation, and in different subcellular organelles and compartments. Neurodegeneration occurs when these protein quality controls are compromised by accumulated pathogenic proteins or aging to an irreversible state. Consequently, several therapeutic strategies, such as targeting the unfolded protein response and autophagy pathways, have been developed to reduce the burden of misfolded proteins and proved useful in animal models. Here, we present a brief overview of the molecular mechanisms involved in maintaining proteostatic networks, along with some examples linking dysregulated proteostasis to neuronal diseases.

Deficiency of the RNA-binding protein ELAVL1/HuR leads to the failure of endogenous and exogenous neuroprotection of retinal ganglion cells.

ELAVL1/HuR is a keystone regulator of gene expression at the posttranscriptional level, including stress response and homeostasis maintenance. The aim of this study was to evaluate the impact of hur silencing on the age-related degeneration of retinal ganglion cells (RGC), which potentially describes the efficiency of endogenous neuroprotection mechanisms, as well as to assess the exogenous neuroprotection capacity of hur-silenced RGC in the rat glaucoma model. The study consisted of in vitro and in vivo approaches. In vitro, we used rat B-35 cells to investigate, whether AAV-shRNA-HuR delivery affects survival and oxidative stress markers under temperature and excitotoxic insults. In vivo approach consisted of two different settings. In first one, 35 eight-week-old rats received intravitreal injection of AAV-shRNA-HuR or AAV-shRNA scramble control. Animals underwent electroretinography tests and were sacrificed 2, 4 or 6 months after injection. Retinas and optic nerves were collected and processed for immunostainings, electron microscopy and stereology. For the second approach, animals received similar gene constructs. To induce chronic glaucoma, 8 weeks after AAV injection, unilateral episcleral vein cauterization was performed. Animals from each group received intravitreal injection of metallothionein II. Animals underwent electroretinography tests and were sacrificed 8 weeks later. Retinas and optic nerves were collected and processed for immunostainings, electron microscopy and stereology. Silencing of hur induced apoptosis and increased oxidative stress markers in B-35 cells. Additionally, shRNA treatment impaired the cellular stress response to temperature and excitotoxic insults. In vivo, RGC count was decreased by 39% in shRNA-HuR group 6 months after injection, when compared to shRNA scramble control group. In neuroprotection study, the average loss of RGCs was 35% in animals with glaucoma treated with metallothionein and shRNA-HuR and 11.4% in animals with glaucoma treated with metallothionein and the scramble control shRNA. An alteration in HuR cellular content resulted in diminished photopic negative responses in the electroretinogram. Based on our findings, we conclude that HuR is essential for the survival and efficient neuroprotection of RGC and that the induced alteration in HuR content accelerates both the age-related and glaucoma-induced decline in RGC number and function, further confirming HuR's key role in maintaining cell homeostasis and its possible involvement in the pathogenesis of glaucoma.

Global ambient particulate matter pollution and neurodegenerative disorders: a systematic review of literature and meta-analysis.

Previous studies on particulate matter (PM) exposure and neurodegenerative disorders showed inconsistent results, and few studies systematically examined the long-term effect of PM on neurodegenerative diseases, including all-cause dementia, Alzheimer's disease, Parkinson's disease, vascular dementia, amyotrophic lateral sclerosis, and cognitive function decline. We systematically searched for published studies in PubMed, Embase, Cochrane Library, and Web of Science up to October 31, 2022. To facilitate a comparison of effect sizes from different studies, we standardized units across studies to a 10μg/m3 increase for PM. Heterogeneity was assessed by Cochran's Q test and I2 statistic. Publication bias was evaluated using funnel plots and Egger's tests. Subgroup analysis, meta-regression, and sensitivity analysis were performed. The protocol for this review was registered with PROSPERO (CRD42021277112). Of the 3403 originally identified studies, a meta-analysis was finally performed in 49 studies. The results showed that there was a significant positive association between long-term PM2.5 exposure and all-cause dementia, Alzheimer's disease as well as Parkinson's disease, with pooled OR of 1.30 (95%CI: 1.14, 1.47, I2 = 99.3%), 1.65 (95%CI: 1.37, 1.94, I2 = 98.2%), and 1.17 (95%CI: 1.00, 1.33, I2 = 91.8%). A positive association between PM10 and vascular dementia was observed (OR = 1.12, 95%CI: 1.04, 1.21, I2 = 0.0%). Association between PM exposure and decreased cognitive function score was found. Our results highlight the important role of PM pollution, particularly PM2.5, in the risk of age-related neurodegenerative diseases and cognitive function decline.

Age-related changes in peripheral T-cell subpopulations in elderly individuals: An observational study.

The age-related decline in T-cell function among elderly individuals remains unclear. We thus investigated the interrelationship between T-cell subsets and age to identify the changes in T-cell phenotypes and develop an age prediction model for the elderly population. A total of 127 individuals aged >60 years were divided into three groups (youngest-old group, 61-70 years, n = 34; middle-old group, 71-80 years, n = 53; and oldest-old group, ≥ 81 years, n = 40). The percentage of CD8+CD28- cells (P = 0.001) was highest in the oldest-old group and then followed by the middle-old group, while the youngest-old group was the lowest. Both females and males demonstrated significant decreases in the absolute counts of CD4+CD45RA+ cells (P = 0.020; P = 0.002) and CD8+CD28+ cells (P = 0.015; P = 0.005) with age. Multivariate linear regression showed that the percentage of CD8+CD28- cells (P < 0.001) was an independent predictor of aging after adjusting for sex, body mass index, hospitalization duration, smoking, drinking, chronic medical illness, and medications at admission. In conclusion, our results suggest that aging in elderly individuals is accompanied by a decrease in the counts of T-cell subpopulations. CD8+CD28- cells may be potential targets for elderly individuals in antiaging-related immunosenescence.

Photoactivatable senolysis with single-cell resolution delays aging.

Strategies that can selectively eliminate senescent cells (SnCs), namely senolytics, have been shown to promote healthy lifespan. However, it is challenging to achieve precise, broad-spectrum and tractable senolysis. Here, we integrate multiple technologies that combine the enzyme substrate of senescence-associated β-galactosidase (SA-β-gal) with fluorescence tag for the precise tracking of SnCs, construction of a bioorthogonal receptor triggered by SA-β-gal to target and anchor SnCs with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy (PDT). We generate KSL0608-Se, a photosensitive senolytic prodrug, which is selectively activated by SA-β-gal. In naturally-aged mice, KSL0608-Se-mediated PDT prevented upregulation of age-related SnCs markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice. We therefore provide a strategy to monitor and selectively eliminate SnCs to regulate aging.

Long-term administration of CU06-1004 ameliorates cerebrovascular aging and BBB injury in aging mouse model

BackgroundAge-related changes in the cerebrovasculature, including blood–brain barrier (BBB) disruption and vascular dementia, are emerging as potential risks for many neurodegenerative diseases. Therefore, the endothelial cells that constitute the cerebrovasculature may play key roles in preventing brain injury. Our previous study showed that CU06-1004, an endothelial cell dysfunction blocker, prevented vascular leakage, enhanced vascular integrity in ischemic reperfusion injury, and promoted the normalization of tumor vasculature. Here, we evaluated the effects of CU06-1004 on age-related cerebrovascular functional decline in the aged mouse brain.ResultsIn this study, we investigated the protective effects of CU06-1004 against oxidative stress–induced damage in human brain microvascular endothelial cells (HBMECs). HBMECs were treated with hydrogen peroxide (H2O2) to establish an oxidative stress–induced model of cellular injury. Compared with H2O2 treatment alone, pretreatment of HBMECs with CU06-1004 considerably reduced oxidative stress–induced cytotoxicity, reactive oxygen species generation, senescence-associated β-galactosidase activity, senescence marker expression, and the expression levels of inflammatory proteins. Based on the observed cytoprotective effects of CU06-1004 in HBMECs, we examined whether CU06-1004 displayed protective effects against cerebrovascular aging in mice. Long-term administration of CU06-1004 alleviated age-associated cerebral microvascular rarefaction and cerebrovascular senescence in the aged mouse brain. CU06-1004 supplementation also reduced the extravasation of plasma IgG by improving BBB integrity in the aged mouse brain, associated with reductions in neuronal injury. A series of behavioral tests also revealed improved motor and cognitive functions in aged mice that received long-term CU06-1004 administration.ConclusionsThese findings suggest that CU06-1004 may represent a promising therapeutic approach for delaying age-related cerebrovascular impairment and improving cognitive function in old age.

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.

Myonuclear alterations associated with exercise are independent of age in humans.

Age-related decline in skeletal muscle structure and function can be mitigated by regular exercise. However, the precise mechanisms that govern this are not fully understood. The nucleus plays an active role in translating forces into biochemical signals (mechanotransduction), with the nuclear lamina protein lamin A regulating nuclear shape, nuclear mechanics and ultimately gene expression. Defective lamin A expression causes muscle pathologies and premature ageing syndromes, but the roles of nuclear structure and function in physiological ageing and in exercise adaptations remain obscure. Here, we isolated single muscle fibres and carried out detailed morphological and functional analyses on myonuclei from young and older exercise-trained individuals. Strikingly, myonuclei from trained individuals were more spherical, less deformable, and contained a thicker nuclear lamina than those from untrained individuals. Complementary to this, exercise resulted in increased levels of lamin A and increased myonuclear stiffness in mice. We conclude that exercise is associated with myonuclear remodelling, independently of age, which may contribute to the preservative effects of exercise on muscle function throughout the lifespan. KEY POINTS: The nucleus plays an active role in translating forces into biochemical signals. Myonuclear aberrations in a group of muscular dystrophies called laminopathies suggest that the shape and mechanical properties of myonuclei are important for maintaining muscle function. Here, striking differences are presented in myonuclear shape and mechanics associated with exercise, in both young and old humans. Myonuclei from trained individuals were more spherical, less deformable and contained a thicker nuclear lamina than untrained individuals. It is concluded that exercise is associated with age-independent myonuclear remodelling, which may help to maintain muscle function throughout the lifespan.

Perinatal Obesity Sensitizes for Premature Kidney Aging Signaling.

Chronic Kidney Disease (CKD), a global health burden, is strongly associated with age-related renal function decline, hypertension, and diabetes, which are all frequent consequences of obesity. Despite extensive studies, the mechanisms determining susceptibility to CKD remain insufficiently understood. Clinical evidence together with prior studies from our group showed that perinatal metabolic disorders after intrauterine growth restriction or maternal obesity adversely affect kidney structure and function throughout life. Since obesity and aging processes converge in similar pathways we tested if perinatal obesity caused by high-fat diet (HFD)-fed dams sensitizes aging-associated mechanisms in kidneys of newborn mice. The results showed a marked increase of γH2AX-positive cells with elevated 8-Oxo-dG (RNA/DNA damage), both indicative of DNA damage response and oxidative stress. Using unbiased comprehensive transcriptomics we identified compartment-specific differentially-regulated signaling pathways in kidneys after perinatal obesity. Comparison of these data to transcriptomic data of naturally aged kidneys and prematurely aged kidneys of genetic modified mice with a hypomorphic allele of Ercc1, revealed similar signatures, e.g., inflammatory signaling. In a biochemical approach we validated pathways of inflammaging in the kidneys after perinatal obesity. Collectively, our initial findings demonstrate premature aging-associated processes as a consequence of perinatal obesity that could determine the susceptibility for CKD early in life.