Frontiers in Aging

PurposeFunctional dependence is a multifactorial health condition affecting well-being and life expectancy. To better understand the mechanisms underlying this condition, we aimed to identify the variables that best prospectively classify adults with and without limitations in basic and instrumental activities of daily living. MethodsA filtering approach was used to select the best predictors of functional status from 4,248 candidate predictors collected in 39,927 participants aged 44 to 88 years old at baseline. Several machine learning models using the selected baseline variables (2010-2015) were compared for their ability to classify participants by functional status (dependent vs. independent) at follow up (2018-2021) on a training dataset (n=31,941) of participants from the Canadian Longitudinal Study on Aging. The best performing model was then examined on a test dataset (n=7,986) to confirm sensitivity, specificity, and accuracy. ResultsEighteen candidate baseline variables were identified as the best predictors of functional status at follow up. Logistic regression was the best performing model for classifying participants by functional status and achieved balanced accuracy of 81.9% on the test dataset. The absence of functional limitations at baseline, stronger grip strength, being free of pain and of chronic conditions, being a female, having a drivers license, and good memory were associated with greater odds functionally independence at follow-up. In contrast, older age, psychological distress, walking slowly, being retired, having one or more chronic conditions, and never going for walks were associated with greater odds of functional dependence at follow-up. ConclusionFunctional status can be best prospectively estimated by health condition, age, muscle strength, short-term memory, physical activity, psychological distress, and sex. These predictors can estimate functional status over 6 years ahead with high accuracy. This early identification of people at risk of functional dependence allows sufficient time for the implementation of interventions aiming to delay functional decline.

In an aging population, exergames, a means for simultaneous cognitive-motor training, in a telerehabilitation setting show promise in overcoming treatment accessibility issues. This study aimed to investigate feasibility and effectiveness of a 10-week home-based stepping exergame training program (60 min/week) under remote supervision in older adults as compared to usual care. An international pragmatic randomized controlled trial (RCT) was conducted in Switzerland, Italy, and Cyprus, including 127 older adults aged [≥]60 years, who were randomly allocated to an intervention (n=62) or a control group (n=65). The adherence rate was 101.4%, the attrition rate 11.8%, and the average exergame enjoyment was rated with 69.1{+/-}18.7 out of 100 points. Significant interaction effects were observed in the Go/No-Go test (Q(1, 53.17)=5.44, p=.02) and significant differences between pre- and post-measurements in the intervention group were found when analyzing the 3 study sites separately (ABC (CY, r=.38, p=.05), Go/No-Go (IT, r=3.0, p=.03), Flexi (CH, r=.67, p=.007), TUG (CH, r=.52, p=.04; CY=r.46, p=.02)). Thus, the step-based exergame intervention appeared to be feasible and safe for older adults, supporting its application in out-patient rehabilitation settings. Additionally, it was effective in improving response inhibition. However, to enhance physical functions, especially in non-acute patients, it may be necessary to increase the training load. Trial Registration: ClinicalTrials.gov NCT05751551

Twelve years ago, the Walk Again Project (WAP) introduced a multi-stage neurorehabilitation protocol, the Walk Again Neurorehabilitation Protocol (WANR), which combines virtual reality training with robotic gait systems, both controlled by an EEG-based, non-invasive brain-machine interface (BMI). Training with the WANR led to significant partial neurological and functional recovery in spinal cord injury (SCI) patients. Yet, the neural mechanisms underlying such a recovery remain unknown. Here, we report on the results obtained with an adapted version of the WANR protocol in a larger, randomized, controlled, assessor-blinded, two group clinical trial aimed at evaluating the concurrent morphological and functional brain changes that take place during motor recovery in SCI. A total of 19 ASIA A, SCI patients (age 21 to 59; lesion time 13 months to 25 years) were initially allocated in two groups: a control classical neurorehabilitation (NR, n=9), and an experimental group (WANR, n=10). Later on, four patients that had finished the NR protocol joined the WANR group. Altogether, 14 patients were trained with the WANR (12 completed 9 months of training and two completed 5 months). When compared to the NR group, the WANR group exhibited a significant motor recovery, measured by the Lower Extremity Motor Score (LEMS) and the Walking Scale for Spinal Cord Injury (WISCI), which was detected at 5 months (mean{+/-}SD LEMS= 1.83{+/-}1.19 and WISCI= 5.92{+/-}2.78), but peaked at 9 months (mean{+/-}SD LEMS= 2.75{+/-}1.54 and WISCI= 9.75{+/-}2.14). Overall, 50% of these WANR-trained patients made a transition from ASIA A to ASIA C during this period. Longitudinal brain imaging analysis revealed that chronic SCI induced a widespread reduction in cortical thickness, including a substantial bilateral atrophy (between 15-22%, or 0.4-0.8mm) in many cortical regions in the insula, temporal, frontal, parietal, and even the occipital lobes. These findings are consistent with a variety of cognitive impairments observed in 40-64% of SCI patients. Moreover, they reinforce the hypothesis that SCIs trigger an acceleration of the normal processes of brain aging, which could explain the higher risk that SCI patients have of developing neurodegenerative disorders. Training with the WANR induced a very significant process of cortical plasticity, represented by a significant reversal of cortical atrophy (up to 1mm in the temporal lobe and insula) and an increase in both functional connectivity strength in cerebellar regions and in eigenvector centrality in executive and integrative cortical regions, like the angular gyrus, precuneus, and middle frontal gyrus. Meanwhile, sensorimotor hubs experienced a centrality reduction. This suggests a functional shift from damaged motor loops towards potential compensatory cortical networks. Accordingly, we propose a new mechanism for BMI-induced clinical improvement and raise the hypothesis that the WANR could induce neurologic recovery in other neurological conditions that produce cortical atrophy. Our findings also suggest that BMI training, coupled with virtual reality, and vigorous exercise or robotic-assisted walking, may also help mitigate or delay the normal process of brain aging in elderly patients. Our findings also categorically indicate that there is neither clinical, nor ethical justification for employing highly invasive cortical implants to treat paraplegics, given that non-invasive protocols, like the WANR, may suffice to induce significant neurological and functional gains in those patients with a few months of non-invasive neurorehabilitation.

There has been a markedly renewed interest in factors associated with pneumonia, a leading cause of death worldwide, due to its frequent concurrence with pandemics of influenza and Covid-19 disease. Reported predisposing factors to both bacterial pneumonia and pandemic viral lower respiratory infections are wintertime occurrence, older age, obesity, pre-existing cardiopulmonary conditions and diabetes. Also implicated are age-related neurodegenerative diseases that cause parkinsonism and dementia. We investigated the prevalence of autopsy-proven pneumonia in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study, between the years 2006 and 2019 and before the beginning of the Covid-19 pandemic. Of 691 subjects dying at advanced ages (mean 83.4), pneumonia was diagnosed postmortem in 343 (49.6%). There were 185 subjects without dementia or parkinsonism while clinicopathological diagnoses for the other subjects included 319 with Alzheimers disease dementia, 127 with idiopathic Parkinsons disease, 72 with dementia with Lewy bodies, 49 with progressive supranuclear palsy and 78 with vascular dementia. Subjects with one or more of these neurodegenerative diseases all had higher pneumonia rates, ranging between 50 and 61%, as compared to those without dementia or parkinsonism (40%). In multivariable logistic regression models, male sex and a non-summer death both had independent contributions (ORs of 1.67 and 1.53) towards the presence of pneumonia at autopsy while the absence of parkinsonism or dementia was a significant negative predictor of pneumonia (OR 0.54). Male sex, dementia and parkinsonism may also be risk factors for Covid-19 pneumonia. The apolipoprotein E4 allele, as well as obesity, chronic obstructive pulmonary disease, diabetes, hypertension, congestive heart failure, cardiomegaly and cigarette smoking history, were not significantly associated with pneumonia, in contradistinction to what has been reported for Covid-19 disease.

Exercise can boost physical and cognitive health in older adults. However, there are a lack of accessible exercise programs that foster adherence among older adults. In this study, we aimed to establish the safety and feasibility of APEX, a new exercise program designed to optimize fitness and cognitive gains for older adults, in addition to evaluating its acute physiological effects, and assessing its possible effects on functional fitness and cognition among healthy older adults. APEX utilizes a multimodal progressive high-intensity interval training (HIIT) design, with high-intensity intervals focused on enhancing cardiovascular fitness and muscle strength, and recovery intervals that incorporate balance and mobility exercises. The APEX training was tested in healthy older adults (n=4) over the course of four weeks. Ultimately, APEX was found to be safe and feasible, with no adverse events and high adherence. Participants met heart rate targets for all of the high-intensity exercises, and all intervals had a significant difference in heart rates between high-intensity and recovery periods in linear effects models (p<0.001). Improvements in functional fitness were observed in aerobic endurance, lower body strength, and balance. The intervention was also associated with positive trends in the cognitive domains of information processing, working memory, executive control, and attention. APEX offers a promising alternative to traditional cardiovascular exercise modalities for older adults with additional benefits for functional fitness and cognition. These results encourage further testing of the APEX program in older adults and different clinical populations.

Background/Objective: Common measures of physical activity (PA) based on duration and intensity do not fully capture its complexity. Adding additional PA components of muscle strength, mechanical strain, and turning actions, can provide a more complete view of activity behavior. Furthermore, PA behaviors differ between men and women. Therefore, the goal of this study is to identify and cluster similar long-term PA patterns over time for each PA component, examined separately for men and women. Methods: We used data from 4963 participants (52% women; mean age 66 years, SD = 8.6) of the Longitudinal Aging Study Amsterdam (1992 to 2019). PA component scores were assigned to self-reported activities, and Sequence Analysis with Optimal Matching was used to identify and cluster similar activity patterns over a period of 10 years, separately for each component and stratified by sex. Results: PA components varied by sex and displayed a unique mix of trajectories, including predominately low, medium, or high activity, increasing or decreasing patterns, and trajectories characterized by early or late mortality. Importantly, trajectories remained independent, indicating that changes in one PA component were not linked to changes in others. Conclusion: Older men and women follow distinct and independent long term PA trajectories across components, underscoring that PA behaviour cannot be described by a single dimension. Significance/Implications: The observed independence and heterogeneity of trajectories suggest that muscle strength, mechanical strain, and turning actions capture meaningful and distinct aspects of PA that are not reflected by traditional measures alone. Future PA-strategies could incorporate these dimensions and acknowledge sex-specific patterns to better reflect natural movement. The independence of components suggests that future interventions should target multiple dimensions, as changes in one component may not translate to others. Such an approach may support more tailored and sustainable PA interventions in later life.

Fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) energize the COVID-19 pandemic. The B.1.351 variant carrying the escape mutation E484K in the receptor binding domain is of particular concern due to reduced immunological protection following vaccination. Protection can manifest as early as 10 days following immunization with full protection two weeks following the second dose, but the course is not well-characterized for variants. Here, we investigated the immune transcriptome of six elderly individuals (average age 82 yr.) from an old peoples home, who contracted B.1.351, with four having received the first dose of BNT162b eight to 11 days prior to the onset of COVID-19 symptoms. The patients were hospitalized and received dexamethasone treatment. Immune transcriptomes were established from PBMCs approximately 10 and 35 days after the onset of COVID-19 symptomology. RNA-seq revealed a more intensive immune response in vaccinated patients as compared to unvaccinated ones. Specifically, transcription factors linked to the JAK/STAT pathway, interferon stimulated genes, and genes associated with innate antiviral immunity and COVID-19-SARS-CoV-2 infection were highly enriched in vaccinated patients. This rendered the transcriptomes of the older vaccinated group significantly different than older unvaccinated individuals infected at the same institution and more similar to the immune response of younger unvaccinated individuals (age range 48-62) following B.1.351 infection. All individuals in this study whether vaccinated or not were hospitalized due to B.1.351 infection and one vaccinated patient died illustrating that although an enhanced immune response was documented infection it was insufficient to protect from disease. This highlights the need for maintaining physical distancing and prevention measures throughout the time course of vaccination in older adults.

Summary/AbstractAs people live longer, age-related diseases, like sarcopenia, will become a greater public health concern. We use the model organism C. elegans to better understand the molecular mechanisms behind muscle maintenance. Muscle function is dependent on having properly organized and functioning thick filaments, which are primarily composed of myosin. The myosin head requires the chaperone UNC-45 to initially fold it after translation and is likely used to re-fold back to functionality after thermal or chemical stress induced unfolding. We observe an early onset of sarcopeania when UNC-45 is perturbed during adulthood. We observe that during adult aging, there is a sequential decline of HSP-90, UNC-45, and then myosin. Myosin and UNC-45 protein decline are independent of steady state mRNA levels. Loss of UNC-45 is correlated with an increase in phosphorylation of the protein. By mass spectrometry, S111 was identified as being phosphorylated and this modification may affect binding to HSP-90. A longevity mutant with delayed onset of sarcopenia also shows a delay in the loss of HSP-90, UNC-45, and myosin. We also see a decrease in UNC-45 protein, but not transcript, in an hsp-90 loss of function mutant, suggesting a role for HSP-90 in stabilizing UNC-45. This leads us to propose the model that during aging, a loss of HSP-90 leads to UNC-45 being post translationally modified, such as phosphorylation, and degraded, which then leads to a loss of myosin, and thus muscle mass and function. A better understanding of how myosin and its chaperone proteins are regulated and affected by aging will lead to better preventative care and treatment of sarcopenia and, possibly, the age-related decline of heart muscle function. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/494828v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@1040254org.highwire.dtl.DTLVardef@34f503org.highwire.dtl.DTLVardef@c1cd67org.highwire.dtl.DTLVardef@1945cf9_HPS_FORMAT_FIGEXP M_FIG C_FIG In young adults, under normal conditions the UCS domain of UNC-45 (shown in green) is bound to the myosin head (in red) and the TPR domain (in yellow) is bound to HSP-90 (in purple). Under stress conditions, HSP-90 detaches from the TPR domain, causing a conformational change in UNC-45 that allows the Central domain (in blue) to bind to the myosin neck (in red) resulting in inhibition of the myosin power stroke while the UCS domain protects/re-folds the myosin head. HSP-90 can then rebind the TPR domain, causing the Central domain to release the myosin neck, allowing movement of the myosin motor. However, aged adults experience a loss of HSP-90 and UNC-45 (which has increased post translational modification with aging). The loss of the Myosin chaperones leads to increased aggregation and degradation of Myosin with age.This loss of Myosin at the thick filament results in decline in muscle mass and function, also known as sarcopenia. Note that only the myosin head and neck are shown for simplicity of illustration.

Aging encompasses the natural processes of birth, growth, and aging, during which the functional ability of muscles gradually decreases, leading to the loss of muscle size and reduced exercise performance known as sarcopenia. This condition is closely associated with weakness, osteoporosis, and degenerative diseases, increasing the risk of falls, fractures, metabolic diseases, and mortality due to limitations in physical performance among the elderly. This study investigated the effects of exercise intervention on biological markers related to skeletal muscle mass and functions in conjunction with aging. At age of four or twenty, the C57BL/6 mice were assigned to Young control (Y-Con, n = 10) or exercise training (Y--Exe, n = 10), and Aged control (A-Con, n=10) or exercise training (A-Exe, n = 10). Exercise intervention was performed on a rodent motor-driven treadmill with a frequency of 5 days per week for 8 weeks. As a consequence, exercise intervention in mice resulted in positive changes in IGF-1 signaling and muscle phenotype compared to mice that did not undergo exercise intervention, specifically showing prominent effects in the A-Exe group compared to the A-Con group. The mitigating effects of exercise intervention on age-related skeletal muscle dysfunction were accompanied by enhanced exercise performance and muscle function, as assessed by grip strength and the rotarod test. The current findings support previous studies that have reported the positive effect of exercise intervention in alleviating age-related declines in exercise performance and muscle function in older adults.

Aging-related muscle atrophy and weakness contribute to loss of mobility, falls and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence position physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20-93. Physical activity status conferred partial protection against age-related decline in physical performance. A trend for reduced muscle mitochondrial respiration with aging was observed in inactive but not in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production was unaffected by aging and active participants displayed higher ROS production. In contrast, mitochondrial calcium retention capacity decreased with aging regardless of physical activity status and correlated with muscle mass, performance and the stress-responsive metabokine GDF15. Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.

The knock-out mutation of the unique M13 family member, the Drosophila melanogaster (fruit fly) Neprilysin-like 15 (Nepl15), resulted in marked reductions of glycogen and glycerolipid storage in adult male flies, but a significant increase of glycogen storage in adult female flies, although the mutant flies consumed the same amount of food as the isogenic w1118 controls. The findings prompted us to characterize sex and age-specific effects of Nepl15 knock-out (Nepl15KO) mutation on lifespan, fertility and fecundity, physiology, cytophysiology, and overall health. The current study shows Nepl15 transcripts are expressed in all embryonic stages of the control flies. The mutant embryos show more glycogen storage, likely due to more maternal glycogen deposition in the eggs. Moreover, there are slight increases in the number of eggs laid, the percentage of pupariation, and the percentage of adult fly eclosion from pupae in the Nepl15KO mutant flies. Interestingly, Nepl15KO female, but not male flies, outlive the respective control flies when cultured on a standard diet. The mutant adult females show significantly less Target of Rapamycin (TOR) and more Sirtuin 6 (Sirt6) expression, changes that may synergistically contribute to their lifespan extension. In contrast, mutant males exhibit significant reductions in both TOR and Sirt6 expression, potentially offsetting their effects on longevity. Cellular health is further improved in mutant females, as evidenced by a marked reduction in reactive oxygen species (ROS), associated with a 1.5-fold increase in the Superoxide dismutase 2 (Sod2) expression at 7 days of age. Both sexes demonstrate improved gut barrier integrity at 40 days, with reduced "Smurf" leakage compared to age-matched controls. Optical cardiography reveals that heart rate in 40-day-old mutants is better preserved, resembling that of 7-day-old flies, whereas control flies show a pronounced age-associated decline. Functionally, Nepl15KO males and females outperform controls in a 6-cm climbing assay at 10, 20, 30, and 40 days of age, with the greatest difference observed at day 40. Following a 45-minute exercise bout at 10 rpm, mutant females continue to outperform controls at both 7 and 40 days, indicating preserved neuromuscular performance. Consistently, ATP levels are significantly elevated in 7- and 40-day-old mutant females, but not in mutant males. Interestingly, only 7-day-old mutant males exhibit increased mitochondrial inner membrane potential, which may enable more rapid ATP turnover when energy demand arises. No detectable differences are observed in thoracic muscle or mitochondrial ultrastructure, nor in overall mitochondrial number. However, no observable changes are noticed in the ultrastructure of the thoracic muscle and mitochondria, and the overall number of mitochondria in the mutant flies. Collectively, our findings demonstrate that Nepl15 loss-of-function confers health benefits at cellular, organ, and organismal levels, with pronounced sex-specific differences. However, the mechanisms by which aging mutant males sustain enhanced functional performance remain elusive.

ObjectivesThis study explored the feasibility and preliminary efficacy of a music-based, multicomponent exercise intervention among community-dwelling older adults with mild-to-moderate cognitive impairment. Methods13 older adults aged 85{+/-}9 years with mild-to-moderate cognitive impairment completed multicomponent exercise training for 20 weeks at an independent living facility. Participants received aerobic, resistance, and balance training paired with beat-accentuated music stimulation (BMS). Participants adherence to the training was tracked down and their cognitive and physical functioning and quality of life were assessed at pre- and post-test. Results13 participants attended an average of 4.6 days/week over 20 weeks and reported high satisfaction with the intervention (90.6%). Participants showed significant improvement in global cognition, cognitive processing speed, and walking endurance/aerobic fitness at post-test. ConclusionsThese findings support the feasibility of music-based, multicomponent exercise training for older adults in an independent living facility and set the stage for future studies to test the efficacy of music on physical activity and ensuing health outcomes. Clinical ImplicationsMusic-based, multicomponent exercise training can be beneficial for community-dwelling older adults with mild-to-moderate cognitive decline. BMS can be combined with exercise training to manipulate exercise tempo and may provide a source of motivation to help older adults adhere to exercise.

This cross-sectional study investigated health management, well-being, and pandemic-related perspectives in Shanghainese adults [&ge;]50 years during early and strict COVID-19 control measures. A self-report survey was administered via Wenjuanxing between March-April/2020. Items from the Somatic Symptom Scale, Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 were administered, as well as pandemic-specific questions. 1181 primarily married, retired females participated; Many had hypertension (n=521, 44.1%), coronary artery disease (CAD; n=201, 17.8%) and diabetes (n=171, 14.5%). While most respondents (n=868; 73.5%) were strictly following control measures (including limiting visits with children; n=390, 33.0%) and perceived they could tolerate that beyond 6 months (n=555;47.0%), they were optimistic about the future if control measures were continued (n=969;82.0%), and perceived impact would be temporary (n=646;64.7%). 52 of those with any condition (8.2%) and 19 of those without a condition (3.5%) reported the pandemic was impacting their health. Somatic symptoms were high (29.4{+/-}7.1/36), with Sleep & Cognitive symptoms highest. 24.4% and 18.9% of respondents had elevated depressive and anxious symptoms, respectively; greater distress was associated with lower income (p=0.018), having hypertension (p=0.001) and CAD (p<0.001), more negative perceptions of global COVID-19 control (p=0.004), COVID-19 spread (p[&le;]0.001), impact on life and health (p<0.001), compliance with control measures (p<0.001), and shorter time control measures could be tolerated (p<0.001) in adjusted analyses. In the initial COVID-19 outbreak, most older adults were optimistic and resilient with regard to the epidemic and control measures. However, the distress of older adults is not trivial, particularly in those with health issues.

The current consensus is that 2 doses of mRNA vaccines against SARS-CoV-2 are needed for people without COVID-19 history, while for those who had suffered COVID-19, a single dose may be enough to achieve high levels of immunization. This consensus has been based on results obtained in middle-aged populations, whereas only few data exist for the oldest and most frail adults such as nursing home residents (NH-Res) that is, the population most vulnerable to develop severe forms of COVID-19. In this study, we studied the anti-SARS-CoV-2 IgG(S) level of NH-Res and healthcare workers (HCWs) with or without a history of COVID-19 infection taking into account the time since immunization (COVID-19 and/or vaccination). 654 subjects were analyzed: 397 NH-Res (median age 88, IQR 82-93 years, 75% women) and 257 Health Care Workers (HCWs, median 46, IQR 38-54 years, 81% women). NH-Res and HCWs were classified in one of the following 3 groups: No-COVID history and 2 vaccine shots (COV-NO/2VACC); Yes-COVID history and 1 (COV-YES/1VACC) or 2 (COV-YES/2VACC) vaccine injections. The time-related decrease in IgG (S) in subjects without COVID-19 history, SARS-COV-2 serology would be negative in HCWs approximately 220 days and in residents 180 days after vaccination. This time-related decrease was much slower in those with history of COVID. NH-Res belonging into the COV-NO/2VACC and the COV-YES/1VACC groups showed lower IgG (S) levels than the same groups of HCWs (for both groups, p<0.0001), whereas in the group COV-YES/2VACC, IgG (S) levels were similar in NH-Res and HCWs (p=0.88). These results remained unchanged after adjustment for age and duration since immunization. Thus, in NH-Res, 2 vaccine shots were associated with a more pronounced immune response, whereas in HCWs, 1 or 2 vaccine shots in patients with COVID-19 history did make any difference. These results indicate significant differences in mRNA vaccination between NH-Res and middle-aged controls, and could contribute to the specification of vaccine policy in this very old, frail population.

It has been demonstrated that short-term stress can enhance cellular responses and promote longevity, whereas long-term stress shortens lifespan. Understanding the relationship between short-term and long-term stress could offer new insights into comprehending and modulating age-related diseases. In this study, we investigate this relationship using transcriptomic and metabolomic analyses in the yeast model system (Saccharomyces cerevisiae). We employed three metabolic treatments: firstly, treating yeast cells with threshold levels of benzoic acid for 24 hours (Short-term [ST] Stressed Cells); secondly, treating yeast cells with threshold levels of benzoic acid for 500 hours, with sub-culturing every 24 hours (Long-term [LT] Stressed Cells); and thirdly, allowing the long-term stressed cells to grow for 16 hours without any benzoic acid (Recovered Cells). Here, we propose that aging is an evolutionarily conserved cellular adaptation mechanism in response to long-term stress exposure. Under short-term stressed conditions, prominent lifespan-extending metabolites such as trehalose and metabolites linked to tumor suppression in humans, such as 5-methylthioadenosine, were overexpressed. In contrast, LT Stressed Cells activated genes such as those responsible for epigenetic regulatory enzymes that govern the aging process, and secondary stress response genes, such as heat shock proteins (HSPs) which are associated with adaptation to cell damage but also often associated with aged cells. Chronological lifespan experiments showed that LT stressed cells lived a shorter lifespan compared to ST Stressed Cells. This suggests that the markers of aging (eg. HSPs, certain epigenetic regulators) are expressed in response to long-term stress to enable cell survival but have the long-term effect of reducing lifespan. In support of this hypothesis, we also show that genes exclusively activated in ST Stressed Cells are conserved solely in eukaryotes, while those significantly expressed in LT Stressed Cells (aging related) exhibit high conservation across all domains of life, with a majority having originated from bacteria hinting at the potential evolutionary benefit of aging.

The FOSL2 gene, integral to the AP-1 transcription factor complex, orchestrates cellular responses to stimuli, including immune surveillance and tissue-resident memory T cell differentiation. This study investigates FOSL2s expression dynamics across ages to elucidate its role in aging and age-associated diseases. Leveraging gene expression profiles in response to environmental challenges, we hypothesize that FOSL2 serves as a critical regulator of aging-associated cellular alterations. Utilizing quantitative PCR and RNA sequencing, we charted FOSL2 expression in human bone marrow-derived mesenchymal stromal cells (hMSCs) aged 17-84 years. Statistical analyses reveal a significant negative correlation between FOSL2 expression and age (slope: -0.02442, R-value: -0.41759, P-value: 0.00081), suggesting FOSL2 as a potential biomarker for aging and its involvement in the decline of regenerative capacity. The observed decrease in FOSL2 expression aligns with its role in regulating cellular processes critical in aging. Understanding FOSL2s regulatory network offers insights into aging mechanisms and therapeutic targets for age-related diseases.

Falls are common among older adults and significantly impact their quality of life. Perturbation-based balance training (PBT) is a task-specific intervention designed to improve reactive balance. This systematic review evaluated the efficacy of PBT in reducing falls, injurious falls, and fall risk factors in older adults. PubMed, CINAHL, EMBASE, and Cochrane databases were searched from inception to June 2024. Randomised controlled trials (RCTs) assessing the effects of PBT on falls or fall risk factors, including reactive balance via laboratory-induced perturbations, were included. Two reviewers independently screened studies and extracted data. Meta-analyses were conducted using a random-effects model, and certainty of evidence was assessed using the GRADE approach. Twenty-five RCTs involving 2,659 participants were included. PBT significantly reduced fall rates by 23% (rate ratio [RR]0.77, 95% CI 0.60-0.99; I2=57%, low certainty) and injurious falls by 24% (RR0.76, 95% CI 0.58-0.98; I2=0%) compared to controls. PBT improved reactive balance (e.g., lab-induced falls) but had limited effects on other fall risk factors (e.g., gait). In the dosage subgroup analysis, only PBT programs for at least 6 hours reduced falls by 33%. PBT reduces falls and related injuries, likely through enhanced reactive balance rather than physical improvements. While many PBT programs are low doses ([~]2 hours), higher doses (6+ hours) likely offer greater fall protection. Further high-quality trials using accessible PBT methods are needed to support scalable implementation.

Dysregulated proteostasis, leading to accumulation of misfolded proteins, electron-dense aggregates (lipofuscin, LF), preamyloid oligomers (PAOs), and proteotoxic stress is a hallmark of aging. We investigated how efficiently proteostatic adaptations to chronic cardiac cyclic adenosine monophosphate (cAMP)-dependent stress change with aging in mice harboring marked, cardiac-specific over-expression of adenylyl cyclase VIII (TGAC8). We assessed protein quality control (PQC) mechanisms: ubiquitin proteasome system (UPS), autophagic flux via macroautophagy, and mitophagy in left ventricles (LVs) of TGAC8 and wild type littermates (WT) at 3-4 months and at 17-21 months of age. At 3-4 months of age TGAC8 mice exhibited markers of increased autophagic flux, measured by levels of microtubule-associated protein 1 light chain 3 (LC3), p62, and their phospho-forms in TGAC8 LV; cathepsin L1 activity was also significantly increased. In addition, canonical mitophagy signaling was enhanced, as receptors PARKIN, p62S405 and p62S351 were all upregulated, confirming a more efficient proteostasis in TGAC8 at 3-4 months vs WT. In advanced age, however, the PQC mechanisms were overwhelmed by proteotoxic stress, manifested in insufficient proteasome activity and an unbalanced autophagic flux (accelerated for markers such as LC3A in the context of a slower overall flux), leading to an increase in the accumulation of protein aggregates (increased ratio of insoluble/soluble protein fractions). Although both canonical (PARKIN, p62S405 and p62S351 receptors) and non-canonical (FKBP8 receptor) mitophagy signaling were upregulated in advanced age in TGAC8, mitophagy was markedly impaired and mitochondrial dysfunction increased. Accumulation of LF bodies, of brownish-to-black pigments, and of LC3+ and p62+-inclusions of aberrant sizes, of desmin cardiac preamyloid oligomers (PAOs) and of cleaved desmin, tagged for ubiquitination, were all increased in TGAC8 compared to young TGAC8. In contrast, the rate of protein synthesis and levels of soluble aggregates were reduced in aged vs young TGAC8, a sign of "normal" aging. Thus, increased proteostatic mechanisms maintain cardiac health in TGAC8 in youth (3-4 months), but long-term exposure to chronic cardiac stress, imposed by sustained activation of the AC/cAMP/PKA/Ca2+ signaling axis, results in severely dysregulated proteostasis in TGAC8 vs WT mice, associated with proteostatic insufficiency and increased cardiomyopathy that leads to accelerated cardiac aging. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/553128v3_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@73ff64org.highwire.dtl.DTLVardef@1842158org.highwire.dtl.DTLVardef@1a92684org.highwire.dtl.DTLVardef@1fe596_HPS_FORMAT_FIGEXP M_FIG C_FIG

Aging is associated with an increased risk of frailty, disability, comorbidities, institutionalization, falls, fractures, hospitalization, and mortality. Searching for strategies to delay the degenerative changes associated with aging and frailty is interesting. We treated old animals intravenously with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement of several functional parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function. Frailty index analysis showed that 40% of old control mice were frail, whereas none of the old ADSCs-sEVs treated mice were. Molecular and structural benefits in muscle and kidney accompanied this functional improvement. ADSCs-sEVs induced pro-regenerative effects and a decrease in oxidative stress, inflammation, and senescence markers. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSCs-sEVs and their metabolome changed to a youth-like pattern. Finally, we gained some insight into the miRNAs contained in sEVs that might be, at least in part, responsible for the effects observed. We propose that young sEVs treatment can be beneficial against frailty and therefore can promote healthy aging.

Declining functional capacity, both physical and cognitive, is a consequence of aging. However, exercise is a promising intervention to mitigate normal age-related decline. While numerous studies have elucidated the benefits of exercise per se, less well-studied is the effect of high intensity interval training (HIIT) on a middle-aged population. Our primary purpose was to assess the effect of three months of HIIT on physical and cognitive performance in middle-aged (17-month-old) male C57BL/6J mice, compared to sedentary controls. We hypothesized that exercised mice would be resistant to any decline in cognitive and physical ability, both measured pre- and post-intervention. To measure physical function, we used the well-validated CFAB (comprehensive functional assessment battery) scoring system comprised of determinants including voluntary wheel running, inverted cling, grip test, treadmill max speed, and rotarod. We measured cognition with open field, novel object recognition, y-maze, and puzzle box. Further measures of sarcopenia/frailty included body composition (MRI) and in vivo contractile physiology (plantar flexor torque). Training resulted in significant aerobic capacity improvements for the HIIT group, increasing treadmill time by 28%, while the SED group demonstrated a 41.4% decline in treadmill time. However, no significant differences in cognitive function were determined. Contrary to our previous research in other age groups, the current study found a negligible effect of HIIT on body composition. We note that at 17 months old, mice did not experience any evidence of cognitive deterioration in either group over the three-month period, thus explaining the lack of exercise effect. We found that HIIT had less influence on either physical or cognitive function than we expected, which may be because function in this age group is stable. Future work will investigate older adult cognitive response to HITT at ages where there is well-documented cognitive decline.