A silver bullet for ageing medicine?: clinical relevance of T-cell checkpoint receptors in normal human ageing.

Immunosenescence describes dysregulation of the immune system with ageing manifested in both the innate and adaptive immunity, including changes in T-cell checkpoint signaling. Through complex and nuanced process, T-cells lose excitatory signaling pathways and upregulate their inhibitory signaling, leading to ineffective immune responses that contribute to the formation of the ageing phenotype. Here we expand on the expression, function, and clinical potential of targeting the T-cell checkpoint signaling in age and highlight interventions offering the most benefits to older adults' health. Notably, modifications in vaccination such as with mTOR inhibitors show immediate clinical relevance and good tolerability. Other proposed treatments, including therapies with monoclonal antibodies fail to show clinical efficacy or tolerability needed for implementation at present. Although T-cell co-signaling fits a valuable niche for translational scientists to manage immunosenescence, future study would benefit from the inclusion of older adults with multiple long-term conditions and polypharmacy, ensuring better applicability to actual patients seen in clinical settings.

Characterization of cellular senescence in aging skeletal muscle.

Senescence is a cell fate that contributes to multiple aging-related pathologies. Despite profound age-associated changes in skeletal muscle (SkM), whether its constituent cells are prone to senesce has not been methodically examined. Herein, using single cell and bulk RNA-sequencing and complementary imaging methods on SkM of young and old mice, we demonstrate that a subpopulation of old fibroadipogenic progenitors highly expresses p16 Ink4a together with multiple senescence-related genes and, concomitantly, exhibits DNA damage and chromatin reorganization. Through analysis of isolated myofibers, we also detail a senescence phenotype within a subset of old cells, governed instead by p2 Cip1 . Administration of a senotherapeutic intervention to old mice countered age-related molecular and morphological changes and improved SkM strength. Finally, we found that the senescence phenotype is conserved in SkM from older humans. Collectively, our data provide compelling evidence for cellular senescence as a hallmark and potentially tractable mediator of SkM aging.

Prevalence and factors associated with poor performance in the 5-chair stand test: findings from the Cognitive Function and Ageing Study II and proposed Newcastle protocol for use in the assessment of sarcopenia.

BACKGROUND: Poor performance in the 5-chair stand test (5-CST) indicates reduced lower limb muscle strength. The 5-CST has been recommended for use in the initial assessment of sarcopenia, the accelerated loss of muscle strength and mass. In order to facilitate the use of the 5-CST in sarcopenia assessment, our aims were to (i) describe the prevalence and factors associated with poor performance in the 5-CST, (ii) examine the relationship between the 5-CST and gait speed, and (iii) propose a protocol for using the 5-CST. METHODS: The population-based study Cognitive Function and Ageing Study II recruited people aged 65 years and over from defined geographical localities in Cambridgeshire, Newcastle, and Nottingham. The study collected data for assessment of functional ability during home visits, including the 5-CST and gait speed. We used multinomial logistic regression to assess the associations between factors including the SARC-F questionnaire and the category of 5-CST performance: fast (<12 s), intermediate (12-15 s), slow (>15 s), or unable, with slow/unable classed as poor performance. We reviewed previous studies on the protocol used to carry out the 5-CST. RESULTS: A total of 7190 participants aged 65+ from the three diverse localities of Cognitive Function and Ageing Study II were included (54.1% female). The proportion of those with poor performance in the 5-CST increased with age, from 34.3% at age 65-69 to 89.7% at age 90+. Factors independently associated with poor performance included positive responses to the SARC-F questionnaire, physical inactivity, depression, impaired cognition, and multimorbidity (all P < 0.005). Most people with poor performance also had slow gait speed (57.8%) or were unable to complete the gait speed test (18.4%). We found variation in the 5-CST protocol used, for example, timing until a participant stood up for the fifth time or until they sat down afterwards. CONCLUSIONS: Poor performance in the 5-CST is increasingly common with age and is associated with a cluster of other factors that characterize risk for poor ageing such as physical inactivity, impaired cognition, and multimorbidity. We recommend a low threshold for performing the 5-CST in clinical settings and provide a protocol for its use.

The feasibility of muscle mitochondrial respiratory chain phenotyping across the cognitive spectrum in Parkinson's disease.

INTRODUCTION: There has been little work on the relationship between sarcopenia, a progressive skeletal muscle disorder, and age-related neurodegenerative diseases such as Parkinson's disease (PD). OBJECTIVES: We aimed to determine: 1) the feasibility of characterizing skeletal muscle across a range of cognitive function in PD; 2) if muscle mitochondrial respiratory chain (MRC) function and content are preserved in older adults with PD. METHODS: Sarcopenia was defined using handgrip strength, chair rise and bioimpedance analysis. MRC function was assessed using phosphorous magnetic resonance spectroscopy (MRS) by estimating τ1/2 PCr (s) (phosphocreatine half-time recovery) in the calf muscles following a bout of aerobic exercise. Biopsy of the vastus lateralis muscle was performed, and MRC content assessed by fluorescent immunohistochemistry for porin and components of MRC Complexes I and IV. RESULTS: Nine participants (78% male; mean age 79.9; PD duration 3.3 years) were recruited. Four had cognitive impairment. Six participants had probable sarcopenia. Eight participants completed MRS and had mean (SD) τ1/2 PCr of 37.8 (7.6) seconds, suggesting preserved mitochondrial function. Muscle biopsies were obtained in all and the procedure was well tolerated. Porin Z-score, a proxy for mitochondrial mass, was lower than expected compared to controls (0-89% of fibres with low porin). There was a small amount of Complex I (0.16-4.59%) and Complex IV (0-3.79%) deficiency. CONCLUSIONS: Detailed phenotyping, muscle biopsy and imaging was feasible and acceptable across a spectrum of cognitive function in PD. Sarcopenia was relatively common and may be associated with lower mitochondrial mass and low levels of MRC deficiency.

Sarcopenia, long-term conditions, and multimorbidity: findings from UK Biobank participants.

BACKGROUND: Sarcopenia, the loss of muscle strength and mass, predicts adverse outcomes and becomes common with age. There is recognition that sarcopenia may occur at younger ages in those with long-term conditions (LTCs) as well as those with multimorbidity (the presence of two or more LTCs), but their relationships have been little explored. Our aims were to describe the prevalence of sarcopenia in UK Biobank, a large sample of men and women aged 40-70 years, and to explore relationships with different categories of LTCs and multimorbidity. METHODS: We used data from 499 046 participants in the baseline of UK Biobank. Our main outcome was probable sarcopenia based on maximum grip strength below sex-specific cut-points. Participants' LTCs were recorded during an interview and categorized against a hierarchy. We used logistic regression to examine the independent associations between each category of LTCs and probable sarcopenia, including adjustment for age, sex, and body mass index. We also examined the association with multimorbidity. RESULTS: Probable sarcopenia had an overall prevalence of 5.3% and increased with age. The categories with the strongest associations with probable sarcopenia were musculoskeletal/trauma [OR 2.17 (95% CI: 2.11, 2.23)], endocrine/diabetes [OR 1.49 (95% CI: 1.45, 1.55)], and neurological/psychiatric [OR 1.39 (95% CI: 1.34, 1.43)] LTCs. Almost half of the sample (44.5%) had multimorbidity, and they were at nearly twice the odds of probable sarcopenia [OR 1.96 (95% CI: 1.91, 2.02)] compared with those without. CONCLUSIONS: We have shown an overall prevalence of 5.3% of probable sarcopenia at ages 40-70 in UK Biobank. The risk of probable sarcopenia was higher in those with some categories of LTCs, suggesting that these groups may stand to benefit from assessment of sarcopenia, during mid-life as well as old age.

Contribution of protein intake and its interaction with physical activity to transitions between disability states and to death in very old adults: the Newcastle 85+ Study.

INTRODUCTION: Growth in the number of very old (≥ 85 years) adults will likely lead to increased prevalence of disability. Our aim was to determine the contribution of protein intake, and the interaction between protein intake and physical activity (PA), to the transition between disability states and to death in the very old using the Newcastle 85+ Study. METHODS: The analytic sample comprised of 717 older adults aged 85 years at baseline and living in the community. Protein intake was estimated with 2 × 24-h multiple pass recalls (24 h-MPR) at baseline. Disability was measured as difficulty performing 17 activities of daily living (ADL) at baseline, at 18, 36, and 60 months, and defined as having difficulties in one or more ADL. The contribution of protein intake [g/kg adjusted body weight/day (g/kg aBW/d)] to transition probabilities to and from disability, and to death over 5 years was examined by multi-state models adjusted for key health covariates. RESULTS: Participants were expected to spend 0.8 years (95% CI 0.6-1.0) disability-free and 2.8 years (95% CI 2.6-2.9) with disability between the ages 85 and 90 years. One unit increase in protein intake (g/kg aBW/d) halved the likelihood of incident disability (HR 0.44, 95% CI 0.24-0.83) but not for other transitions. Similar reductions in disability incidence were also found in individuals with protein intake ≥ 0.8 (HR 0.50, 95% CI 0.31-0.80) and ≥ 1 g/kg aBW/d (HR 0.49, 95% CI 0.33-0.73). Participants with high PA and protein intake ≥ 1 g/kg aBW/d were less likely to transition from disability-free to disability than those within the same PA level but with protein intake < 1 g/kg aBW/d (HR 0.45, 95% CI 0.28-0.72). CONCLUSION: Higher protein intake, especially in combination with higher physical activity, may delay the incidence of disability in very old adults.

Mediterranean diet adherence and cognitive function in older UK adults: the European Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC-Norfolk) Study.

BACKGROUND: In Mediterranean countries, adherence to a traditional Mediterranean dietary pattern (MedDiet) is associated with better cognitive function and reduced dementia risk. It is unclear if similar benefits exist in non-Mediterranean regions. OBJECTIVES: The aims of this study were to examine associations between MedDiet adherence and cognitive function in an older UK population and to investigate whether associations differed between individuals with high compared with low cardiovascular disease (CVD) risk. METHODS: We conducted an analysis in 8009 older individuals with dietary data at Health Check 1 (1993-1997) and cognitive function data at Health Check 3 (2006-2011) of the European Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC-Norfolk). Associations were explored between MedDiet adherence and global and domain-specific cognitive test scores and risk of poor cognitive performance in the entire cohort, and when stratified according to CVD risk status. RESULTS: Higher MedDiet adherence defined by the Pyramid MedDiet score was associated with better global cognition (ß ± SE = -0.012 ± 0.002; P < 0.001), verbal episodic memory (ß ± SE = -0.009 ± 0.002; P < 0.001), and simple processing speed (ß ± SE = -0.002 ± 0.001; P = 0.013). Lower risk of poor verbal episodic memory (OR: 0.784; 95% CI: 0.641, 0.959; P = 0.018), complex processing speed (OR: 0.739; 95% CI: 0.601, 0.907; P = 0.004), and prospective memory (OR: 0.841; 95% CI: 0.724, 0.977; P = 0.023) was also observed for the highest compared with the lowest Pyramid MedDiet tertiles. The effect of a 1-point increase in Pyramid score on global cognitive function was equivalent to 1.7 fewer years of cognitive aging. MedDiet adherence defined by the Mediterranean Diet Adherence Screener (MEDAS) score (mapped through the use of both binary and continuous scoring) showed similar, albeit less consistent, associations. In stratified analyses, associations were evident in individuals at higher CVD risk only (P < 0.05). CONCLUSIONS: Higher adherence to the MedDiet is associated with better cognitive function and lower risk of poor cognition in older UK adults. This evidence underpins the development of interventions to enhance MedDiet adherence, particularly in individuals at higher CVD risk, aiming to reduce the risk of age-related cognitive decline in non-Mediterranean populations.

Grip strength and inflammatory biomarker profiles in very old adults.

Background: weak grip strength (GS) and chronic inflammation have been implicated in the aetiology of sarcopenia in older adults. Given the interrelationships between inflammatory biomarkers, a summary variable may provide better insight into the relationship between inflammation and muscle strength. This approach has not been investigated in very old adults (aged ≥85) who are at highest risk of muscle weakness. Methods: we used mixed models to explore the prospective association between GS over 5 years in 845 participants in the Newcastle 85+ Study, and inflammatory components identified by principal component analysis (PCA). Cut-offs of ≤27 kg (men) and ≤16 (women) were used to define sub-cohorts with weak and normal GS at each assessment. Results: PCA identified three components, which explained 70% of the total variance in seven baseline biomarkers. Basal interleukin-6 (IL-6) and tumour necrosis factor (TNF-α) had the highest loadings on Component 1; stimulated IL-6 and TNF-α and homocysteine the highest on Component 2; high-sensitivity C-reactive protein (hsCRP) loaded positively and albumin negatively to Component 3. In adjusted mixed models, only Component 3 was associated with GS. One SD increase of Component 3 was associated with a 0.41 kg lower GS initially (P = 0.03) in all participants, but not with GS decline over time. Similar conclusions held for those in the weak and normal GS sub-cohorts. Conclusion: an inflammatory profile including hsCRP and albumin was independently associated with baseline GS. Future studies linking inflammatory profiles and muscle strength are needed to corroborate these findings in older adults.

Predicting Risk of Cognitive Decline in Very Old Adults Using Three Models: The Framingham Stroke Risk Profile; the Cardiovascular Risk Factors, Aging, and Dementia Model; and Oxi-Inflammatory Biomarkers.

OBJECTIVES: To examine the Framingham Stroke Risk Profile (FSRP); the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score, and oxi-inflammatory load (cumulative risk score of three blood biomarkers-homocysteine, interleukin-6, C-reactive protein) for associations with cognitive decline using three cohort studies of very old adults and to examine whether incorporating these biomarkers with the risk scores can affect the association with cognitive decline. DESIGN: Three longitudinal, population-based cohort studies. SETTING: Newcastle-upon-Tyne, United Kingdom; Leiden, the Netherlands; and Lakes and Bay of Plenty District Health Board areas, New Zealand. PARTICIPANTS: Newcastle 85+ Study participants (n = 616), Leiden 85-plus Study participants (n = 444), and Life and Living in Advanced Age, a Cohort Study in New Zealand (LiLACS NZ Study) participants (n = 396). MEASUREMENTS: FSRP, CAIDE risk score, oxi-inflammatory load, FSRP incorporating oxi-inflammatory load, and CAIDE risk score incorporating oxi-inflammatory load. Oxi-inflammatory load could be calculated only in the Newcastle 85+ and the Leiden 85-plus studies. Measures of global cognitive function were available for all three data sets. Domain-specific measures were available for the Newcastle 85+ and the Leiden 85-plus studies. RESULTS: Meta-analysis of pooled results showed greater risk of incident global cognitive impairment with higher FSRP (hazard ratio (HR) = 1.46, 95% confidence interval (CI) = 1.08-1.98), CAIDE (HR = 1.53, 95% CI = 1.09-2.14), and oxi-inflammatory load (HR = 1.73, 95% CI = 1.04-2.88) scores. Adding oxi-inflammatory load to the risk scores increased the risk of cognitive impairment for the FSRP (HR = 1.65, 95% CI = 1.17-2.33) and the CAIDE model (HR = 1.93, 95% CI = 1.39-2.67). CONCLUSION: Adding oxi-inflammatory load to cardiovascular risk scores may be useful for determining risk of cognitive impairment in very old adults.

Prevalence and incidence of sarcopenia in the very old: findings from the Newcastle 85+ Study.

INTRODUCTION: Recognition that an older person has sarcopenia is important because this condition is linked to a range of adverse outcomes. Sarcopenia becomes increasingly common with age, and yet there are few data concerning its descriptive epidemiology in the very old (aged 85 years and above). Our aims were to describe risk factors for sarcopenia and estimate its prevalence and incidence in a British sample of the very old. METHODS: We used data from two waves (2006/07 and 2009/10) of the Newcastle 85+ Study, a cohort born in 1921 and registered with a Newcastle/North Tyneside general practice. We assessed sarcopenia status using the European Working Group on Sarcopenia in Older People (EWGSOP) definition. Grip strength was measured using a Takei digital dynamometer (Takei Scientific Instruments Ltd., Niigata, Japan), gait speed was calculated from the Timed Up and Go test, and lean mass was estimated using a Tanita-305 body fat analyzer. We used logistic regression to examine associations between risk factors for prevalent sarcopenia at baseline and incident sarcopenia at follow-up. RESULTS: European Working Group on Sarcopenia in Older People sarcopenia was present in 21% of participants at baseline [149/719 participants, mean age 85.5 (0.4) years]. Many participants had either slow gait speed or weak grip strength (74.3%), and hence measurement of muscle mass was frequently indicated by the EWGSOP definition. Incidence data were available for 302 participants, and the incident rate was 3.7 cases per 100 person years at risk. Low Standardized Mini-Mental State Examination, lower occupational social class, and shorter duration of education were associated with sarcopenia at baseline, while low muscle mass was associated with incident sarcopenia. Low body mass index (BMI) was a risk factor for both in a graded fashion, with each unit decrease associated with increased odds of prevalent [odds ratio (OR) 1.29, 95% confidence interval (CI): 1.21, 1.37] and incident (OR 1.20, 95% CI: 1.08, 1.33) sarcopenia. CONCLUSIONS: To our knowledge, this is the first study to describe prevalence and incidence of EWGSOP sarcopenia in the very old. Low BMI was a risk factor for both current and future sarcopenia; indeed, there was some evidence that low BMI may be a reasonable proxy for low lean mass. Overall, the high prevalence of sarcopenia among the very old suggests that this group should be a focus for future research.

What do we know about the nutritional status of the very old? Insights from three cohorts of advanced age from the UK and New Zealand.

Very old people (referred to as those aged 85 years and over) are the fastest growing age segment of many Western societies owing to the steady rise of life expectancy and decrease in later life mortality. In the UK, there are now more than 1·5 million very old people (2·5 % of total population) and the number is projected to rise to 3·3 million or 5 % over the next 20 years. Reduced mobility and independence, financial constraints, higher rates of hospitalisation, chronic diseases and disabilities, changes in body composition, taste perception, digestion and absorption of food all potentially influence either nutrient intake or needs at this stage of life. The nutritional needs of the very old have been identified as a research priority by the British Nutrition Foundation's Task Force report, Healthy Ageing: The Role of Nutrition and Lifestyle. However, very little is known about the dietary habits and nutritional status of the very old. The Newcastle 85+ study, a cohort of more than 1000 85-year olds from the North East of England and the Life and Living in Advanced Age study (New Zealand), a bicultural cohort study of advanced ageing of more than 900 participants from the Bay of Plenty and Rotorua regions of New Zealand are two unique cohort studies of ageing, which aim to assess the spectrum of health in the very old as well as examine the associations of health trajectories and outcomes with biological, clinical and social factors as each cohort ages. The nutrition domain included in both studies will help to fill the evidence gap by identifying eating patterns, and measures of nutritional status associated with better, or worse, health and wellbeing. This review will explore some of this ongoing work.

Antihypertensive drug use and risk of cognitive decline in the very old: an observational study - the Newcastle 85+ Study.

OBJECTIVES: Older adults are a fast growing group in society and are at high risk of hypertension, cognitive decline and dementia. Antihypertensive drugs, particularly calcium channel blockers (CCB), have been associated with a decreased risk of cognitive decline and dementia. We used observational data to examine the association between antihypertensive drug class and change in cognitive function. METHODS: The Newcastle 85+ Study is a population-based cohort study recruiting individuals aged 85 (born in 1921) via general/family practices in Newcastle/North Tyneside, United Kingdom. Data, including blood pressure, antihypertensive drug use and cognitive function [assessed using the Standardized Mini-Mental State Exam (SMMSE)], were collected at baseline and 3-year follow-up. RESULTS: The study population comprised 238 participants with a diagnosis of hypertension, prescribed antihypertensive drug treatment and with baseline and follow-up SMMSE assessment. There was an association between CCB use and less cognitive decline over 3 years (rate of decline was lower by 1.29 SMMSE points (95% confidence interval 0.16-2.42; P = 0.03) compared with those taking other antihypertensive classes after adjustment for age, sex, years of education, baseline SMMSE score, smoking, BMI, baseline blood pressure, and incident cerebrovascular event. This finding was even stronger in the cognitively intact (SMMSE >24), wherein rate of cognitive decline was lower by 1.33 SMMSE points (95% confidence interval 0.30-2.37; P = 0.01), but was not seen for other antihypertensive classes. CONCLUSION: Findings provide support for an association between CCB use and a lower rate of cognitive decline in very old adults with hypertension.

Alzheimer Abeta peptide induces chromosome mis-segregation and aneuploidy, including trisomy 21: requirement for tau and APP.

Both sporadic and familial Alzheimer's disease (AD) patients exhibit increased chromosome aneuploidy, particularly trisomy 21, in neurons and other cells. Significantly, trisomy 21/Down syndrome patients develop early onset AD pathology. We investigated the mechanism underlying mosaic chromosome aneuploidy in AD and report that FAD mutations in the Alzheimer Amyloid Precursor Protein gene, APP, induce chromosome mis-segregation and aneuploidy in transgenic mice and in transfected cells. Furthermore, adding synthetic Abeta peptide, the pathogenic product of APP, to cultured cells causes rapid and robust chromosome mis-segregation leading to aneuploid, including trisomy 21, daughters, which is prevented by LiCl addition or Ca(2+) chelation and is replicated in tau KO cells, implicating GSK-3beta, calpain, and Tau-dependent microtubule transport in the aneugenic activity of Abeta. Furthermore, APP KO cells are resistant to the aneugenic activity of Abeta, as they have been shown previously to be resistant to Abeta-induced tau phosphorylation and cell toxicity. These results indicate that Abeta-induced microtubule dysfunction leads to aneuploid neurons and may thereby contribute to the pathogenesis of AD.