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With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice., Competing Interests: Declaration of interests M.M., V.S., M.P.S., and V.N.G. have filed patents on measuring aging. C.H. is affiliated with the Institute for Biomedical Aging Research, Universität Innsbruck, Austria and an honorary research fellow at the Department of Women’s Cancer, EGA Institute for Women’s Health, University College London, United Kingdom. C.H. and M.W. are shareholders of Sola Diagnostics GmbH and named as inventors on a patent on an epigenetic clock indicative of breast cancer risk. J.N.J. is affiliated with the Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA and the XPRIZE Foundation, Culver City, CA, USA. J.N.J. also serves on the advisory board for the American Federation for Aging Research (AFAR)’s Finding Aging biomarkers by Searching existing Trials (FAST) Initiative and the editorial board of Journals of Gerontology Series A Biological Sciences, eLife, and Experimental Gerontology. D.W.B. is affiliated with the Child Brain Development Network, Canadian Institute for Advanced Research and SocioMed Research Nucleus, Universidad Mayor, Santiago, Chile. D.W.B. also serves on the advisory board for the American Federation for Aging Research (AFAR)’s Finding Aging biomarkers by Searching existing Trials (FAST) Initiative and the editorial board of Journals of Gerontology Series A Biological Sciences and is an inventor of DunedinPACE, a Duke University and University of Otago invention licensed to TruDiagnostic. A.A.C. is a founder, president, and majority shareholder at Oken Health. I.B. is affiliated with the SOMT University of Physiotherapy, Amersfoort, The Netherlands and is a member of the clinical advisory board of Rejuvenate Biomed. M.W. is affiliated with the Institute for Biomedical Aging Research, Universität Innsbruck, Austria. N.B. is the Scientific Director of the American Federation for Aging Research (AFAR), on the board of the executive committee of the Longevity Biotech Association, and advisor on the Board of the Academy for Health and Lifespan Research. M.K. is an employee and shareholder of Optispan Inc., a company developing tools to enable science-based personalized and preventative geromedicine. The Regents of the University of California is the sole owner of a patent application directed at GrimAge and other epigenetic clocks for which S.H. is a named inventor. S.H. is also a founder and paid consultant of the nonprofit Epigenetic Clock Development Foundation that licenses patents surrounding epigenetic clocks. A.B.M. is the Chief Medical Officer of NU. V.N.G. is a scientific advisor to Retro and Dior. M.P.S. is a cofounder and scientific advisor of Personalis, SensOmics, Qbio, January AI, Fodsel, Filtricine, Protos, RTHM, Iollo, Marble Therapeutics, Crosshair Therapeutics, and Mirvie. M.P.S. is also a scientific advisor of Jupiter, Neuvivo, Swaza, and Mitrix. V.S. is co-founder, SAB chair, and head of research of Turn Biotechnologies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Ageing-related low-grade inflammation is suggested to aggravate sarcopenia and frailty. This systematic review investigates the influence that drugs with anti-inflammatory effects (AIDs) have on inflammation and skeletal muscle., Methods: PubMed and Web of Science were systematically screened for articles reporting the effects of AIDs on inflammation on one hand and on muscle mass and/or performance on the other., Results: Twenty-eight articles were included. These articles were heterogeneous in terms of the subjects studied, intervention components, setting, and outcome measures. Articles on older humans with acute inflammation showed evidence that celecoxib and piroxicam could reduce inflammation and improve performance and that ibuprofen improves exercise-induced muscle hypertrophy and gains in strength. In younger humans, only the effects of AIDs combined with exercise were investigated; no significant benefits of non-selective COX-inhibitors were reported, but improved strength gains with etanercept and reduced muscle soreness with celecoxib were noted. Indomethacin increased acute exercise-induced inflammation and reduced satellite cell differentiation in exercising muscle. Most articles did not systematically report occurrences of side effects., Conclusions: Although AIDs showed significant reduction in inflammation-induced muscle weakness in older hospitalised patients with acute inflammation, robust evidence is still lacking. When combined with exercise, AIDs presented a protective effect against age-related loss of muscle mass, thus enhancing muscle mass and performance. The mechanism regulating muscle strength and its mass seems to differ between individuals of old and young age. However, the effects seem drug-specific and dose-dependent and appear to be influenced by subjects' trainability and the clinical context. In addition, the balance between benefits and harm remains unclear., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Decline in physical activity and functioning is commonly observed in the older population and might be associated with biomarkers such as advanced glycation end products (AGEs). AGEs contribute to age-related decline in the function of cells and tissues in normal aging and have been found to be associated with motor function decline. The aim of this study is to investigate the association between the levels of AGEs, as assessed by skin autofluorescence, and the amount of physical activity and loss of physical functioning in older participants., Methods: Cross-sectional data of 5,624 participants aged 65 years and older from the LifeLines Cohort Study were used. Linear regression analyses were utilized to study the associations between skin autofluorescence/AGE levels (AGE Reader), the number of physically active days (SQUASH), and physical functioning (RAND-36). A logistic regression analysis was used to study the associations between AGE levels and the compliance with the Dutch physical activity guidelines (SQUASH)., Results: A statistical significant association between AGE levels and the number of physically active days (β = -0.21, 95% confidence interval: -0.35 to -0.07, p = .004), physical functioning (β = -1.60, 95% confidence interval: -2.64 to -0.54, p = .003), and compliance with the Dutch physical activity guidelines (odds ratio = 0.76, 95% confidence interval: 0.62 to 0.94, p = .010) was revealed., Conclusions: This study indicates that high AGE levels may be a contributing factor as well as a biomarker for lower levels of physical activity and functioning in the older population.

Chronic inflammation and Advanced Glycation End products (AGE) are associated with sarcopenia. Decreased voluntary muscle activation and increased antagonist coactivation can contribute to age-related muscle weakness. The influence of chronic inflammation and AGE in these neuromuscular mechanisms is not clear. We studied whether a relation exists between circulating levels of inflammatory cytokines and AGEs as well as the interplay between agonist and antagonist muscle activation. We studied 64 community-dwelling old subjects, during a maximal isometric voluntary contraction (MVC) and a reaction-time (RT) test of the upper limb. Twenty-five circulating inflammatory biomarkers were determined. Linear regression showed significant relationships between chronic inflammation and six muscle activation parameters. MIP-1β showed a significant negative relation with antagonist coactivation (during MVC) and antagonist muscle activity during pre-movement time (PMT) and movement time (MT) (during RT). A higher level of pentosidine (AGE) was predictive for a longer PMT. We conclude that in older relatively healthy persons antagonist muscle activation is influenced by chronic inflammation, contributing to age-related muscle weakness. Our results also suggest a mechanical and inflammatory influence of pentosidine in upper limb slowing of movement. These findings show novel insight in underlying mechanisms of age-related muscle weakness., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Research underlines the potential of low-load resistance exercise in older adults. However, while the effects of detraining from high-load protocols have been established, it is not known whether gains from low-load training would be better/worse maintained. The current study evaluated the effects of 24weeks of detraining that followed 12weeks of high- and low-load resistance exercise in older adults. Fifty-six older adults (68.0±5.0years) were randomly assigned to leg press and leg extension training at either HIGH load (2×10-15 repetitions at 80% of one-repetition maximum (1-RM)), LOW load (1×80-100 repetitions at 20% of 1-RM), or LOW+ load (1×60 repetitions at 20% of 1-RM, immediately followed by 1×10-20 repetitions at 40% 1-RM). All protocols ended with volitional fatigue. The main outcome measures included mid-thigh muscle volume, leg press 1-RM, leg extension isometric and isokinetic strength, and functional performance. Tests were performed at baseline, post-intervention and after 24weeks of detraining. Results show no effect of load on preservation of muscle volume, which returned to baseline after detraining. Training-induced gains in functional capacity and isometric strength were maintained, independent of load. HIGH and LOW+ were more beneficial than LOW for long-lasting gains in training-specific 1-RM. To conclude, gains in muscle volume are reversed after 24weeks of detraining, independent of load. This emphasises the need for long-term resistance exercise adherence. The magnitude of detraining in neuromuscular and functional adaptations was similar between groups. These findings underline the value of low-load resistance exercise in older age. Clinical Trial Registration NCT01707017., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Geriatric patients with acute infection show increased muscle weakness and fatigability but the relative contribution of central and peripheral factors is unclear. Hospitalised patients with acute infection (82±6years, N=10) and community-dwelling controls (76±6years, N=19) sustained a maximal voluntary isometric contraction of the M. Adductor Pollicis until strength dropped to 50% of its maximal value. Voluntary muscle activation (VA) was assessed before and at the end of the fatigue protocol using twitch interpolation method and muscle activity was monitored using surface electromyography. Twenty-five circulating inflammatory biomarkers were determined. At pre-fatigue, no significant difference in VA was found between groups. VA decreased to similar levels (~50%) at the end of the fatigue protocol with no association with inflammatory biomarkers. In geriatric patients, muscle activity decreased significantly (p<0.05) during the fatigue protocol, whereas it increased in the controls (time∗group interaction p<0.05). The decrease in muscle activity was significantly related to higher levels of inflammation. Although slower muscle contraction and relaxation were significantly related to higher levels of inflammation, no statistical differences were found between groups. Our results confirm that muscle activity is significantly altered in older patients with acute infection and that local processes are involved., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Literature reports on the effects of resistance training on heat shock protein70 (Hsp70) adaptation in older subjects are scarce. Moreover, the optimum training load required to obtain a beneficial adaptation profile is lacking. Therefore, the aim of this study was to determine the effects of resistance training at various external loads on extracellular Hsp70 (eHsp70) resting levels in older humans., Methods: Fifty-six community-dwelling older (68±5years) volunteers were randomized to 12weeks of resistance training (3×/week) at either high-resistance (HIGH, 8 males, 10 females, 2×10-15 repetitions at 80% 1RM), low resistance (LOW, 9 Males, 10 Females, 1×80-100 repetitions at 20% 1RM), or mixed low resistance (LOW+, 9 Males, 10 Females, 1×60 repetitions at 20% 1RM followed by 1×10-20 repetitions at 40% 1RM). Serum was available from 48 out of the 56 participants at baseline and after 12weeks for determination of eHsp70. Mid-thigh muscle volume (computed tomography), muscle strength (1RM & Biodex dynamometer) and physical functioning (including 6min walk distance [6MWD]) were assessed., Results: There was a sex-related dichotomy in the heat shock response to high external load training. We observed a significant decrease in eHsp70 concentration in the HIGH group for female, but not male, subjects. At baseline, men had a larger muscle volume, leg press and leg extension 1RM compared to women (all p<0.001). Also, the 6MWD was significantly higher in men compared to women at baseline. However, this difference disappeared when correcting for height. Moreover, the overall functional performance and physical activity scores were similar in men and women. None of the participants' characteristics nor any of the outcome variables differed between groups at baseline. There was a significant increase in the strength and physical performance parameters in both men and women post-exercise (all p<0.05). Females in the HIGH group clearly demonstrated a larger gain in leg press 1RM and the isometric knee extensor strength compared to females in the LOW group (p=0.036 and p=0.044, respectively). More so, we found an inverse association between the change in eHsp70 levels and improvement in isometric knee extensor strength and 6MWD (r=-0.443, p=0.002 and r=-0.428, p=0.002; respectively) post exercise., Conclusions: Our results show that resistance training at high external load decreases the resting levels of eHsp70 in older females. Whether this reflects a better health status requires further investigation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Sarcopenia is increasingly recognized as a correlate of ageing and is associated with increased likelihood of adverse outcomes including falls, fractures, frailty and mortality. Several tools have been recommended to assess muscle mass, muscle strength and physical performance in clinical trials. Whilst these tools have proven to be accurate and reliable in investigational settings, many are not easily applied to daily practice., Methods: This paper is based on literature reviews performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group on frailty and sarcopenia. Face-to-face meetings were afterwards organized for the whole group to make amendments and discuss further recommendations., Results: This paper proposes some user-friendly and inexpensive methods that can be used to assess sarcopenia in real-life settings. Healthcare providers, particularly in primary care, should consider an assessment of sarcopenia in individuals at increased risk; suggested tools for assessing risk include the Red Flag Method, the SARC-F questionnaire, the SMI method or different prediction equations. Management of sarcopenia should primarily be patient centered and involve the combination of both resistance and endurance based activity programmes with or without dietary interventions. Development of a number of pharmacological interventions is also in progress., Conclusions: Assessment of sarcopenia in individuals with risk factors, symptoms and/or conditions exposing them to the risk of disability will become particularly important in the near future.

Background: During organismal aging, human T-cells shift towards less functional phenotypes, often called senescent cells. As these cells have not been well characterized, we aimed to relate surface markers of human T-cell senescence with characteristics of in vitro cellular aging and to further characterize these cells., Methods: We identified, by flow cytometry, subpopulations of CD8+ T-cells based on CD57 and CD28 expression, and tested them for some markers of cellular senescence, apoptosis, differentiation and homing., Results: Elderly persons presented significantly higher proportions not only of CD28-CD57+, but also of CD28+CD57+ cells. CD28+CD57+ cells had the highest expression of p16, p21, Bcl-2, CD95, CD45RO, CCR5 and PD-1, thereby arguing in favor of a senescent phenotype., Conclusion: Among CD8+ T-lymphocytes, CD28+CD57+ cells represent a subset with some senescent features that are distinct from the CD28-CD57+ cells., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Previously, we showed that prolonged reaction-time (RT) in older persons is related to increased antagonist muscle co-activation, occurring already before movement onset. Here, we studied whether a difference in temporal agonist and antagonist muscle activation exists between young and older persons during an RT-test. We studied Mm. Biceps (antagonist muscle) & Triceps (agonist muscle) Brachii activation time by sEMG in 60 young (26 ± 3 years) and 64 older (80 ± 6 years) community-dwelling subjects during a simple point-to-point RT-test (moving a finger using standardized elbow-extension from one pushbutton to another following a visual stimulus). RT was divided in pre-movement-time (PMT, time for stimulus processing) and movement-time (MT, time for motor response completion). Muscle activation time 1) following stimulus onset (PMAT) and 2) before movement onset (MAT) was calculated. PMAT for both muscles was significantly longer for the older subjects compared to the young (258 ± 53 ms versus 224 ± 37 ms, p=0.042 for Biceps and 280 ± 70 ms versus 218 ± 43 ms for Triceps, p<0.01). Longer agonist muscle PMAT was significantly related to worse PMT and RT in young (respectively r=0.76 & r=0.68, p<0.001) and elderly (respectively r=0.42 & r=0.40, p=0.001). In the older subjects we also found that the antagonist muscle activated significantly earlier than the agonist muscle (-22 ± 55 ms, p=0.003). We conclude that in older persons, besides the previously reported increased antagonist muscle co-activation, the muscle firing sequence is also profoundly altered. This is characterized by a delayed muscle activation following stimulus onset, and a significantly earlier recruitment of the antagonist muscle before movement onset., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Age-related muscle weakness is only partially related to muscle atrophy, due to neuromuscular changes including reduced voluntary muscle activation and antagonist muscle co-activation. The respective contribution of these mechanisms in exercise-induced strength gains at higher age is unclear. Here the literature was systematically reviewed for studies reporting exercise-induced effects on voluntary muscle activation and antagonist muscle co-activation in elderly persons. Seventeen relevant studies were identified, 4 investigated voluntary muscle activation, 8 antagonist muscle co-activation and 5 studies investigated both. Meta-analysis showed an exercise-induced improvement in voluntary activation in plantar flexors (weighted mean difference (WMD) +8.8%, p<0.001), and knee extensors (WMD +1.8%, p<0.001), with greater gains in activation capacity obtained in subjects with lower voluntary activation level prior to the onset of training. We found no significant overall effect of strength training on antagonist co-activation during ankle plantar flexion (WMD +0.6%, p=0.686) or knee extension (WMD -1.1%, p=0.699 for the RCT's and -1.8%, p=0.516 for the non-controlled trials). Based on our results we can conclude that there is evidence for exercise-induced increase in voluntary activation related to strength gains in the lower extremities in elderly persons. The results for exercise-induced effects on antagonist co-activation are inconsistent and more research is necessary to determine its contribution to strength gains following resistance training in elderly persons., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aging is associated with a chronic low-grade inflammatory status that contributes to chronic diseases such as age-related muscle wasting, kidney disease, and diabetes mellitus. Since advanced glycation end products (AGEs) are known to be proinflammatory, this systematic review examined the relation between the dietary intake of AGEs and inflammatory processes. The PubMed and Web of Science databases were screened systematically. Seventeen relevant studies in humans or animals were included. The intervention studies in humans showed mainly a decrease in inflammation in subjects on a low-AGE diet, while an increase in inflammation in subjects on a high-AGE diet was less apparent. About half of the observational studies found a relationship between inflammatory processes and AGEs in food. When the results are considered together, the dietary intake of AGEs appears to be related to inflammatory status and the level of circulating AGEs. Moreover, limiting AGE intake may lead to a decrease in inflammation and chronic diseases related to inflammatory status. Most of the trials were conducted in patients with chronic kidney disease or diabetes, and thus additional studies in healthy individuals are needed. Further investigation is needed to elucidate the effects of lifetime exposure of dietary AGEs on aging and health., (© 2014 International Life Sciences Institute.)

In older persons, vitamin D insufficiency and a subclinical chronic inflammatory status frequently coexist. Vitamin D has immune-modulatory and in vitro anti-inflammatory properties. However, there is inconclusive evidence about the anti-inflammatory role of vitamin D in older subjects. Thus, we investigated the hypothesis of an inverse relationship between 25-hydroxyvitamin D (25(OH)D) and inflammatory markers in a population-based study of older individuals. After excluding participants with high-sensitivity C-reactive protein (hsCRP) ≥ 10 mg/dl and those who were on chronic anti-inflammatory treatment, we evaluated 867 older adults ≥65 years from the InCHIANTI Study. Participants had complete data on serum concentrations of 25(OH)D, hsCRP, tumor necrosis factor (TNF)-α, soluble TNF-α receptors 1 and 2, interleukin (IL)-1β, IL-1 receptor antagonist, IL-10, IL-18, IL-6, and soluble IL-6 receptors (sIL6r and sgp130). Two general linear models were fit (model 1-adjusted for age, sex, and parathyroid hormone (PTH); model 2-including covariates of model 1 plus dietary and smoking habits, physical activity, ADL disability, season, osteoporosis, depressive status, and comorbidities). The mean age was 75.1 ± 17.1 years ± SD. In model 1, log(25OH-D) was significantly and inversely associated with log(IL-6) (β ± SE = -0.11 ± 0.03, p = <0.0001) and log (hsCRP) (β ± SE = -0.04 ± 0.02, p = 0.04) and positively associated with log(sIL6r) (β ± SE = 0.11 ± 0.04, p = 0.003) but not with other inflammatory markers. In model 2, log (25OH-D) remained negatively associated with log (IL-6) (β ± SE = -0.10 ± 0.03, p = 0.0001) and positively associated with log(sIL6r) (β ± SE = 0.11 ± 0.03, p = 0.004) but not with log(hsCRP) (β ± SE = -0.01 ± 0.03, p = 0.07). 25(OH)D is independently and inversely associated with IL-6 and positively with sIL6r, suggesting a potential anti-inflammatory role for vitamin D in older individuals.

Ageing is associated with a chronic low-grade inflammatory profile (CLIP). Physical exercise could circumvent the deleterious effects of CLIP by influencing circulating inflammatory mediators and neurotrophic growth factors. This study aimed at assessing whether 12 weeks of progressive strength training (PST) influences circulating brain-derived neurotrophic factor (BDNF), interleukin (IL)-6 and IL-10 in elderly individuals. Forty community-dwelling persons aged 62-72 years participated. Twenty participants were assigned to 12-week PST (70-80 % of maximal strength, three times per week). Matched control individuals (n = 20) maintained daily activity levels. Serum was collected for BDNF, IL-6 and IL-10 assay from all participants before and after 12 weeks (for PST subjects 24-48 h after the last training). In PST, muscle strength was significantly improved (+49 % for leg extension, p = 0.039), and basal IL-6 levels significantly reduced (p = 0.001), which remained unchanged in control (p = 0.117). No significant change in BDNF was observed in PST subjects (p = 0.147) or control (p = 0.563). IL-10 was below the detection limit in most subjects. Gender and health status did not influence the results. Our results show that after 12-week PST, muscle performance improved significantly, and basal levels of IL-6 were significantly decreased in older subjects. However, serum BDNF was not altered. The lack of an observable change in BDNF might be due to a short-lived BDNF response, occurring acutely following exercise, which might have been washed out when sampling. Furthermore, blood levels of BDNF may not reflect parallel increases that occur locally in the brain and muscle. These hypotheses need confirmation by further studies.

Muscle adaptations can be induced by high-resistance exercise. Despite being potentially more suitable for older adults, low-resistance exercise protocols have been less investigated. We compared the effects of high- and low-resistance training on muscle volume, muscle strength, and force-velocity characteristics. Fifty-six older adults were randomly assigned to 12 weeks of leg press and leg extension training at either HIGH (2×10-15 repetitions at 80% of one repetition maximum (1RM)), LOW (1×80-100 repetitions at 20% of 1RM), or LOW+ (1×60 repetitions at 20% of 1RM, followed by 1×10-20 repetitions at 40% of 1RM). All protocols ended with muscle failure. Leg press and leg extension of 1RM were measured at baseline and post intervention and before the first training session in weeks 5 and 9. At baseline and post intervention, muscle volume (MV) was measured by CT-scan. A Biodex dynamometer evaluated knee extensor static peak torque in different knee angles (PT(stat90°), PT(stat120°), PT(stat150°)), dynamic peak torque at different speeds (PT(dyn60°s)(-1), PT(dyn180°s)(-1), PT(dyn240°s)(-1)), and speed of movement at 20% (S20), 40% (S40), and 60% (S60) of PTstat90°. HIGH and LOW+ resulted in greater improvements in 1RM strength than LOW (p<0.05). These differences were already apparent after week 5. Similar gains were found between groups in MV, PT(stat), PT(dyn60°s)(-1), and PT(dyn180°s)(-1). No changes were reported in speed of movement. HIGH tended to improve PT(dyn240°s)(-1) more than LOW or LOW+ (p=0.064). In conclusion, high- and low-resistance exercises ending with muscle failure may be similarly effective for hypertrophy. High-resistance training led to a higher increase in 1RM strength than low-resistance training (20% of 1RM), but this difference disappeared when using a mixed low-resistance protocol in which the resistance was intensified within a single exercise set (40% of 1RM). Our findings support the need for more research on low-resistance programs in older age, in particular long-term training studies and studies focusing on residual effects after training cessation., (© 2013.)

Objective: Since dual energy X-ray absorptiometry (DXA) cannot distinguish between different adipose tissue (AT) deposits, it remains unclear how DXA-derived body composition variables relate to anatomical tissue (sub)compartments. The aim of the present study was to compare and relate regional DXA variables with absolute tissue masses obtained by computer tomography (CT) scanning of the lower limbs in elderly persons., Methods: Eleven well-preserved white Caucasian adults (seven male and four female cadavers) with a median age of 79.0 years (ranging from 68 to 96 years) were fully scanned with DXA and CT. Separate densities of skin tissue, AT, muscle tissue and bone were obtained by hydrostatic weighing., Results: The leg DXA-variables were significantly related (rho-values between 0.60 and 0.98, P < 0.01) to CT-derived tissue counterparts, but showed significant systematic differences except for subcutaneous AT mass (P = 0.773). After controlling for other AT depots, fat as measured by DXA (fat(DXA)) related only to intermuscular AT (rho = 0.82, P < 0.01) in males and to subcutaneous AT (rho = 0.84, P < 0.05) in females., Conclusion: Although significantly interrelated, DXA and CT variables should not be used interchangeably since they have different quantitative and physiological significance. Our results suggest that fat(DXA) represents different parts of AT depots in elderly men and women. Since DXA is not appropriate for assessing tissue variability cautious clinical interpretation is warranted., (© 2013.)

CD28-, CD57+ and KLRG1+ are cell surface markers that have been used to describe senescent T-lymphocytes in humans. However, the relationship among these phenotypes during aging, and their relationship with the concept of in vitro cellular aging have not been well established. Using five-colour flow cytometry, we analyzed peripheral blood T-lymphocytes for their expression of CD28, CD57 and KLRG1 in 11 young (Y) and 11 old (O) apparently healthy human subjects. The proportions of CD28- and CD57+ cells were significantly higher among the T-cell populations of O compared to Y subjects; the proportion of KLRG1+ cells was significantly higher only among CD8+ cells. Populations that were more frequent in the elderly participants were characterised as CD28+ CD57+, CD28- CD57+ or CD28- CD57-. The expression of p16 and p21, considered as markers for in vitro senescence, was higher in CD28+ CD57+ cells than in other subpopulations in both age groups. The expression of p21 was age-related, which was not the case for p16. Thus, although both p16 and p21 are involved in T-cell senescence, they appear to behave differently. CMV infection and shifts in subpopulations are unlikely as explanations of the observed differences. Their higher levels of p16 and p21 expression, coupled with their higher prevalence in the elderly participants make CD28+ CD57+ cells the subpopulation of T-cells most closely corresponding to the concept of senescent cells.

Worldwide, people engage insufficiently in physical activity, particularly subjects aged 80 years and over. For optimal life-style campaigns, knowledge of motivators and barriers for physical activity is mandatory. Given their specific needs, it is conceivable that these would be different for the oldest old compared to younger subjects. Pubmed, Web of Science and Psychinfo were systematically screened for articles reporting motivators and barriers for physical activity. Papers were excluded if data regarding elderly aged >79 years were absent. Forty-four relevant articles were included, involving a total of 28,583 subjects. Sixty one motivators and 59 barriers for physical activity in the elderly were identified, including those who are relevant for persons aged 80 years and over. Based on the results of our literature review, we recommend that when promoting physical activity in the oldest old, special attention is paid to the health benefits of physical activity, to the subject's fears, individual preferences and social support, and to constraints related to the physical environment. However, no studies were found exclusively describing people aged 80 years and over, and future research is necessary to differentiate the barriers or motivators that are specific for the oldest old from those of younger elderly., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Multiple causes contribute to the prolonged reaction-times (RT) observed in elderly persons. The involvement of antagonist muscle co-activation remains unclear. Here the Mm. Biceps and Triceps Brachii activation in 64 apparently healthy elderly (80 ± 6 years) and 60 young (26 ± 3 years) subjects were studied during a simple RT-test (moving a finger using standardized elbow-extension from one pushbutton to another following a visual stimulus). RT was divided in pre-movement-time (PMT, time for stimulus processing) and movement-time (MT, time for motor response completion). RT-performance was significantly worse in elderly compared to young; the slowing was more pronounced for MT than PMT (respectively 101 ± 10 ms and 41 ± 6 ms slower, p<0.01). Elderly subjects showed significantly higher (p<0.01) antagonist muscle co-activation during the PMT-phase, which was significantly related to worse MT and RT (p<0.01). During the MT-phase, antagonist muscle co-activation was similar for both groups. It can be concluded that increased antagonist muscle co-activation in elderly persons occurs in an early phase, already before the start of the movement. These findings provide further understanding of the underlying mechanisms of age-related slowing of human motor performance., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Heat shock proteins (Hsp) are ubiquitously synthesised in virtually all species and it is hypothesised that they might have beneficial health effects. Recent studies have identified circulating Hsp as an important mediator in inflammation - the effects of low-grade inflammation in the aging process are overwhelming. While much is known about intracellular Hsp70, scant data exist on circulating Hsp70 in the aging context. Therefore, the objectives of this study were to investigate the effect of age and disease on circulating Hsp70 and, in particular, to evaluate the association between circulating Hsp70 and inflammatory parameters., Results: Serum Hsp70, Interleukin (IL) -10, IL-6 and Tumor Necrosis Factor (TNF) alpha concentrations were determined in 90 hospitalised geriatric patients (aged 83 ± 6 years) and in 200 community-dwelling control subjects (100 elderly, aged 74 ± 5 years, and 100 young, aged 23 ± 3 years). In the community-dwelling elderly, serum Hsp70 and IL-10 concentrations were significantly lower and IL-6 was significantly higher when compared to healthy young control subjects. Elderly patients presenting inflammation (CRP serum levels ≥5 mg/L) showed significantly (p = 0.007) higher Hsp70 values; and Hsp70 correlated positively (p < 0.001) with IL-6 and CRP, but not with TNF-alpha or IL-10. A significant association was also noted between Hsp70 levels and the degree of dependency and cognitive decline in geriatric patients., Conclusions: The present data provide new evidence that serum concentration of Hsp70 decreases with age in a normal population. Our study also shows that higher levels of Hsp70 are associated with inflammation and frailty in elderly patients.

Purpose: To investigate the reliability of a 3D-accelerometry based gait analysis, and its correlates with clinical status and fall-risk., Methods: Forty elderly subjects presenting with increased fall-risk (OFR), 41 elderly controls (OC) and 40 young controls (aged 80.6±5.4, 79.1±4.9 and 21.6±1.4 years respectively) underwent three gait evaluations (two assessors in random order) each containing two walks of 18 m with a DynaPort MiniMod accelerometer on the pelvis. Intra- and inter-observer reliability of gait speed, step-time asymmetry, mediolateral and craniocaudal step and stride regularity were determined by ICC and CV of standard error of measurement (CV(SEM)). Relationships with cognition (MMSE), dependency, grip strength, muscle endurance, and fall-risk (fall-history, timed-get-up-and-go and Tinetti-test) were analysed in elderly participants., Results: Reliability for single walk was low (ICC<0.70, 11%0.80, CV(SEM)<7%), but high (ICC>0.70, 4%

We have used a multiplex bead array assay to detect simultaneously 25 different circulating cytokines in 35 control subjects (young versus old) and 29 patients (young versus old) with acute infection. Intracellular PBMC levels of heat shock proteins (Hsp) were determined using flow cytometry. Levels of MIG and IL-6 were higher in the elderly normal subjects and patients, respectively, compared to their young counterparts. Hsp32, Hsp70 and Hsp90 were higher in elderly compared to young normal subjects. This difference disappeared for patients with inflammation who had increased levels of Hsp32, Hsp70 and Hsp90 compared to normal subjects. Most striking, a different pattern of association between cytokines and Hsp was noticed in healthy elderly subjects compared to the other groups of participants. It is concluded that age-related stress, possibly oxidative, which can down-regulate cytokine production with a concomitant up-regulation of Hsp production, could be involved in this differential pattern of association.

The global aging population faces significant health challenges, including an increasing vulnerability to disability due to natural aging processes. Wearable lower limb exoskeletons (LLEs) have emerged as a promising solution to enhance physical function in older individuals. This systematic review synthesizes the use of LLEs in alignment with the WHO's healthy aging vision, examining their impact on intrinsic capacities and functional abilities. We conducted a comprehensive literature search in six databases, yielding 36 relevant articles covering older adults (65+) with various health conditions, including sarcopenia, stroke, Parkinson's Disease, osteoarthritis, and more. The interventions, spanning one to forty sessions, utilized a range of LLE technologies such as Ekso®, HAL®, Stride Management Assist®, Honda Walking Assist®, Lokomat®, Walkbot®, Healbot®, Keeogo Rehab®, EX1®, overground wearable exoskeletons, Eksoband®, powered ankle–foot orthoses, HAL® lumbar type, Human Body Posturizer®, Gait Enhancing and Motivation System®, soft robotic suits, and active pelvis orthoses. The findings revealed substantial positive outcomes across diverse health conditions. LLE training led to improvements in key performance indicators, such as the 10 Meter Walk Test, Five Times Sit-to-Stand test, Timed Up and Go test, and more. Additionally, enhancements were observed in gait quality, joint mobility, muscle strength, and balance. These improvements were accompanied by reductions in sedentary behavior, pain perception, muscle exertion, and metabolic cost while walking. While longer intervention durations can aid in the rehabilitation of intrinsic capacities, even the instantaneous augmentation of functional abilities can be observed in a single session. In summary, this review demonstrates consistent and significant enhancements in critical parameters across a broad spectrum of health conditions following LLE interventions in older adults. These findings underscore the potential of LLE in promoting healthy aging and enhancing the well-being of older adults. [ABSTRACT FROM AUTHOR]

Background: Fatigue might influence the losses in activities of daily living (ADL). When fatigue parameters are present before the experience of losses in ADL and gait speed they can be used as early warning signals. This study aimed to explore the predictive value of muscle endurance and fatigue on changes in ADL and gait speed in community-dwelling older adults aged 80 and over.Methods: 324 community-dwelling older adults aged 80 and older of the BUTTERFLY study were assessed after one year for muscle endurance, self-perceived fatigue, Activities of Daily Living and gait speed. Exploratory factor analysis (EFA) was performed to explore, whether there is an underlying arrangement of the fatigue parameters. Mediating logistic regression analyses were used to investigate whether muscle endurance mediated by self-perceived fatigue predicts decline in gait speed and ADL after one year follow-up.Results: Exploratory factor analysis indicated a 2-factor model (muscle endurance factor and self-perceived fatigue factor) and had a moderate fit (X 2: 374.81, df: 2, CFI; 0.710, TLI: 0.961, RSMEA(90%): 0.048 (0.00-0.90)). Muscle endurance mediated by self-perceived fatigue had an indirect effect on the prediction of decline in Basal- (-0.27), Instrumental-ADL (-0.25) and gait speed (-0.28) after one year follow-up.Conclusion: This study showed that low muscle endurance combined with high self-perceived fatigue can predict changes in ADL after one-year follow-up. These parameters might be very suitable for use in evaluating intrinsic capacity and can help to reduce the limitations in clinical usage of the vitality domain in the framework of intrinsic capacity. [ABSTRACT FROM AUTHOR]

Objectives: Previously, we developed and validated an easy test to measure muscle fatigability during sustained maximal handgrip contraction in older persons using a Martin Vigorimeter device. This study aimed at validating the equation to estimate grip work (GW) during sustained maximal handgrip contraction, by monitoring continuously the grip strength (GS) decay using a Jamar Dynamometer-like (JD) device.Design: Cross sectional, explorative study.Setting: Data collection took place at The National Research Centre for the Working Environment in Copenhagen, Denmark.Participants: 962 subjects, belonging to a subgroup of the Copenhagen Aging and Midlife Biobank, were enrolled.Methods: GS was recorded continuously during sustained maximal contraction until it dropped to 50% of its maximum and fatigue resistance (FR, time to fatigue) was noted. GW, area under the force-time curve, was compared to its estimate which was calculated as GWestimated=GSmax*0.75*FR.Results: Excellent correlation was found between GWestimated and GWmeasured (R2=0.98 p<0.001). The equation slightly overestimated GW by 6.04 kg*s (95% CI[-0.08, 12.15]) with a coefficient of variation method error of 6%.Conclusion: GW estimation is a valid parameter reflecting muscle work output during a sustained maximal grip effort in healthy middle-aged community-dwelling persons when using a JD. GW estimation is a promising outcome parameter in comprehensive geriatric assessment and its validation for commonly used instruments in geriatric practice will increase its clinical implementation. [ABSTRACT FROM AUTHOR]

Background Exercise effectiveness is related to adherence, compliance and drop-out. The aim of this study is to investigate if exercise-induced pain and health status are related to these outcomes during two exercise programs in knee osteoarthritis patients. Methods Symptomatic knee osteoarthritis patients were randomly allocated to a walking or strengthening program (N = 19/group). At baseline, patients were categorized according to their health status. Exercise adherence and compliance were calculated and drop-out rate was registered. For exercise-induced pain, patients rated their pain on an 11-point numeric rating scale (NRS) before and after each training session. Before each session the maximal perceived pain of the last 24 h (NRS max24 ) was assessed. Patients rated their global self-perceived effect (GPE) on a 7-point ordinal scale after the intervention period. Results 53% of the participants felt they improved after the program, 6 patients dropped out. The mean adherence and compliance rates were higher than .83 in both groups. Worse health and higher exercise-induced pain were seen in drop-outs. NRS max24 during the first 3 weeks did not significantly increase compared to baseline, but correlated negatively with adherence during the home sessions (−.56, p < .05). Lower adherence during supervised sessions was significantly related with higher pre-exercise pain scores (ρ = −.35, p < .05). Conclusion Patients who drop-out show a worse health condition and higher exercise-induced pain levels compared to patients that retained the program. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence for the significant involvement of inflammatory processes in the development of muscle wasting in old age. Therefore, any disease accompanied by inflammation can be threatening to the muscle function in geriatric patients.Methods: Sixty-three hospitalized geriatric patients (42 female, 21 male; mean age 84.2 +/- 5.7 years) were monitored weekly for muscle function (grip strength, fatigue resistance, shoulder extension strength, and hip extension strength) and for concentration of circulating C-reactive protein (CRP), fibrinogen, interleukin 6 (IL-6), and tumor necrosis factor-alpha alpha (TNF-alpha).Results: On the basis of circulating CRP and fibrinogen concentrations, 42 patients were categorized on admission as inflammatory and 21 as noninflammatory. Inflammatory patients presented significantly weaker grip strength, shoulder extension strength, and a worse fatigue resistance than did noninflammatory patients. These muscle functions were negatively correlated with the concentrations of circulating CRP and IL-6, but not with fibrinogen or TNF-alpha. In noninflammatory patients, the fatigue resistance improved significantly during the first week of hospitalization. In patients admitted with inflammation, no improvement of muscle function was observed. Patients who remained inflammatory for 2 weeks or more presented a significant worsening of fatigue resistance.Conclusions: Geriatric hospitalized patients presenting with inflammation show significantly worse muscle functions, which do not improve during hospitalization despite adequate treatment of the primary disease. Reduced strength and fatigue resistance are significantly related to the concentration of circulating CRP and IL-6. Standard treatment of the underlying illness and classic physical therapy are not sufficient to normalize the skeletal muscle strength and fatigue resistance in these hospitalized patients. [ABSTRACT FROM AUTHOR]

Abstract: Background:: Acute inflammation has a negative effect on the muscular system in elderly patients, compromising the outcome of the underlying disease. Objective:: The aim of this study was to evaluate the effect of cyclooxygenase-2 (COX-2) inhibition on muscle performance and mobility in hospitalized elderly patients with acute inflammation of infectious origin. Methods:: In this single-blind, controlled trial, consecutively hospitalized elderly patients (age ≥70 years) with inflammation (C-reactive protein [CRP] levels ≥10 mg/L) due to acute infection were randomly assigned to receive 2 weeks of treatment with the COX-2—selective inhibitor celecoxib, acetaminophen, or no supplementary medication (control). The following variables were assessed at baseline and at 1 and 2 weeks'' follow-up: muscle fatigue resistance (primary outcome measure); grip strength and mobility (secondary outcome measures); and levels of the acute-phase markers CRP, interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor—alpha (TNF-α), and transforming growth factor—beta (TGF-β) as explanatory variables. Results:: Forty-three consecutively hospitalized elderly patients (31 women, 12 men; mean [SD] age, 84 [6] years) were enrolled. Fourteen patients received celecoxib, 14 received acetaminophen, and 15 received no supplementary medication. The change in fatigue resistance was significantly different between groups (P = 0.021, Kruskal-Wallis chi-square test), with significantly greater improvement in patients receiving celecoxib compared with the acetaminophen and control groups (63% increase from baseline; P &#60; 0.05). There were no significant between-group differences in changes in grip strength, mobility, IL-1β, IL-6, TNF-α, or TGF-β. The changes in levels of IL-10 differed significantly between groups (P = 0.020, Kruskal-Wallis chi-square test), with greater improvement in the celecoxib group compared with the acetaminophen group (P = 0.032). Conclusion:: The results of this study suggest that COX-2—selective inhibition has a beneficial effect on muscle fatigue resistance in hospitalized elderly patients with acute inflammation of infections origin. However, until further trials are conducted, the use of COX-2—selective inhibitors for this indication is nor recommended. [Copyright &y& Elsevier]

Impaired motor function is a prominent characteristic of aging. Inflammatory processes and oxidative stress from advanced glycation end-products are related to impaired motor function and could plausibly be a contributing factor to the pathogenesis of paratonia, a specific motor disorder in people with dementia. Severe paratonia results in a substantial increase of a caretaker's burden and a decrease in the quality of life. The pathogenesis of paratonia is not well understood, and no effective interventions are available to combat it. Intensive glycaemic control, reducing oxidative stress, possibly combined with a low AGE diet and AGE targeting medication may be the key method for preventing advanced glycation end-product accumulation and reducing the inflammatory burden as well as possibly postponing or preventing paratonia. • Inflammatory processes from AGEs are related to paratonia. • AGE induced viscoelastic changes in muscle tissue might be responsible. • Glycaemic control could possibly be an effective way to address AGE accumulation and prevent paratonia. • This new perspective on paratonia is a beginning point for further research. [ABSTRACT FROM AUTHOR]

Abstract Introduction Older people suffer more often and from more severe infections than do younger people. Several studies have shown a correlation between higher white blood cell count (WBCC) and the presence of infection. The usefulness of increased WBCC to assess the presence of infection in geriatric patients is debated. To answer this question, we investigated the correlation between the total and differential WBCC and documented infection in hospitalized geriatric individuals. Population and methods Clinical data (medical history, comorbidities, treatments, geriatric syndromes) and biological parameters were collected from 166 hospitalized geriatric patients (67–106 yrs) presenting with acute inflammation (C-reactive protein (CRP) > 10 mg/l) and were compared according to the presence/absence of infection. Results The mean WBCC was not significantly different (p = 0.71) according to the presence of infection or not, although the mean CRP level was higher in the infected group compared to the non-infected group (p = 0.0019). In regression analyses, the presence of infection was not associated with an increase in total and differential WBCC. Additionally, we found a positive correlation between cardiovascular risk factor and diseases (CVRF & diseases) and WBCC. Conclusion In geriatric patients, WBCC is not a reliable biomarker for infection; however, combined with CRP, it represents a marker of cardiovascular disorders. Highlights • A normal absolute WBCC does not rule out infection in geriatric patients. • This study suggests that white blood cell count is not a reliable marker of infection in geriatric patients. • However, combined with CRP, WBCC represents a marker of cardiovascular disorders. [ABSTRACT FROM AUTHOR]

Immunosenescence is a remodeling of the immune system occurring with aging that leads to an increased susceptibility to auto-immunity, infections and reduced vaccination response. A growing consensus supports the view that physical exercise may counteract immunosenescence and improve the immune response. Unfortunately, evidence regarding the effects of exercise on markers of cellular immunosenescence lacked uniformity at the time of an extensive literature review in 2016. Moreover, exercise-induced effects in older adults were underrepresented compared to young adults or completely lacking, such as for senescent T-cells and apoptosis of T-lymphocytes. The aim of this systematic literature study was to collect and appraise newly available data regarding exercise-induced changes on immunosenescence-related markers of immune cells and compare this against data that was already available in 2016. Systematic reviewing of newly available data in the field of exercise immunology provides additional evidence for the effect of exercise on immunosenescence-related cellular markers. Importantly, this review provides evidence for the effect of long-term exercise on senescent T-lymphocytes in older adults. Additionally, newly retrieved evidence shows an acute exercise-induced mobilization of naïve and memory cells in older adults. In general, data regarding long-term exercise-induced effects in older adults remain scarce. Noteworthy was the high number of articles describing exercise-induced effects on regulatory T-cells. However exercise-induced effects on this cell type are still inconclusive as some articles reported an exercise-induced up- or downregulation, while others reported no effects at all. Numerous studies on Natural Killer cell counts did not provide uniformity among data that was already available. Recent data regarding dendritic cells mostly described an increase after exercise. Overall, our literature update highlights the major influence of the type and intensity of exercise on immunosenescence-related markers, especially in older adults. • New evidence regarding effect of exercise on cellular immunosenescence-related markers • Inclusion of 55 articles after systematic screening of Pubmed and Web of Science • New evidence to prescribe physical exercise to counter immunosenescence • Evidence for exercise-induced removal of senescent T-cells in older adults • Data regarding long-term exercise-induced effects in older adults remain scarce [ABSTRACT FROM AUTHOR]

Ageing is characterized by a low-grade chronic inflammation marked by elevated circulating levels of inflammatory mediators. This chronic inflammation occurring in the absence of obvious infection has been coined as inflammageing and represents a risk factor for morbidity and mortality in the geriatric population. Also, with ageing, important perturbations in the gut microbiota have been underlined and a growing body of literature has implicated age-related gut dysbiosis as contributing to a global inflammatory state in the elderly. Notwithstanding, very little attention has been given to how gut microbiota impact inflammageing. Here, we investigate the available evidence regarding the association between inflammageing and gut microbiota during ageing. PubMed, Web of Science and Scopus were systematically screened, and seven relevant articles in animals or humans were retrieved. The animal studies reported that Parabacteroides, Mucispirillum, Clostridium and Sarcina positively associate with the pro-inflammatory MCP-1 while Akkermansia, Oscillospira, Blautia and Lactobacillus negatively correlate with MCP-1. Furthermore, "aged"-type microbiota were associated with increased levels of IL6, IL-10, Th1, Th2, Treg, TNF-α, TGF-β, p16, SAMHD1, Eotaxin, and RANTES; activation of TLR2, NF-κB and mTOR; and with decreased levels of cyclin E and CDK2. On the other hand, the study on humans demonstrated that bacteria of the phylum Proteobacteria exhibited a positive correlation with IL-6 and IL-8, while Ruminococcus lactaris et rel. portrayed a negative correlation with IL-8. We conclude that changes in "aged"-type gut microbiota are associated with inflammageing. [ABSTRACT FROM AUTHOR]