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

Milk intake across adulthood and muscle strength decline from mid- to late life: the MRC National Survey of Health and Development

Milk is a source of several nutrients which may be beneficial for skeletal muscle. Evidence that links lower milk intake with declines in muscle strength from midlife to old age is lacking. We used data from the MRC NSHD to test sex-specific associations between milk consumption from age 36 to 60-64 years, low grip strength (GS) or probable sarcopenia, and GS decline from age 53 to 69 years. We included 1340 men and 1383 women with at least one measure of both milk intake and GS. Milk intake was recorded in 5-day food diaries (ages 36, 43, 53 and 60-64), and grand mean of total, reduced-fat and full-fat milk each categorised in thirds (T1 (lowest) to T3 (highest), g/day). GS was assessed at ages 53, 60-64, and 69, and probable sarcopenia classified at age 69. We employed logistic regression to examine the odds of probable sarcopenia, and multilevel models to investigate decline in GS in relation to milk intake thirds. Compared with T1, only T2 (58.7-145.2g/day) of reduced-fat milk was associated with lower odds of sex-specific low GS at age 69 (OR (95% CI): 0.59 (0.37, 0.94), p=0.03). In multilevel models, only T3 of total milk (≥237.5g/day) was associated with stronger GS in midlife in men (β (95% CI) = 1.82 (0.18, 3.45)kg, p=0.03) compared with T1 (≤152.0g/day), but not with GS decline over time. A higher milk intake across adulthood may promote muscle strength in midlife in men. Its role in muscle health in late life needs further examination

Mediterranean diet adherence and cognitive function in older, UK adults: The 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. Objective To examine associations between MedDiet adherence and cognitive function in an older, UK population. To investigate whether associations differed between individuals with high versus low cardiovascular disease (CVD) risk. Design 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 of Cancer, 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 (β±SE=-0.012±0.002; P<0.001), verbal episodic memory (β±SE=-0.009±0.002; P<0.001), and simple processing speed (β±SE=-0.002±0.001; P=0.013). Lower risk of poor verbal episodic memory (OR(95%CI)=0.784 (0.641,0.959); P=0.018), complex processing speed (OR(95%CI)=0.739 (0.601,0.907); P=0.004), and prospective memory (OR(95%CI)=0.841 (0.724,0.977); P=0.023) was also observed for the highest versus lowest Pyramid MedDiet tertiles. The effect of a one-point increase in Pyramid score on global cognitive function was equivalent to 1.7 fewer years of cognitive ageing. MedDiet adherence defined by the MEDAS score (mapped using 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

Nutrition and frailty:Opportunities for prevention and treatment

Frailty is a syndrome of growing importance given the global ageing population. While frailty is a multifactorial process, poor nutritional status is considered a key contributor to its pathophysiology. As nutrition is a modifiable risk factor for frailty, strategies to prevent and treat frailty should consider dietary change. Observational evidence linking nutrition with frailty appears most robust for dietary quality: for example, dietary patterns such as the Mediterranean diet appear to be protective. In addition, research on specific foods, such as a higher consumption of fruit and vegetables and lower consumption of ultra-processed foods are consistent, with healthier profiles linked to lower frailty risk. Few dietary intervention studies have been conducted to date, although a growing number of trials that combine supplementation with exercise training suggest a multi-domain approach may be more effective. This review is based on an interdisciplinary workshop, held in November 2020, and synthesises current understanding of dietary influences on frailty, focusing on opportunities for prevention and treatment. Longer term prospective studies and well-designed trials are needed to determine the causal effects of nutrition on frailty risk and progression and how dietary change can be used to prevent and/or treat frailty in the future

The Role of Lipoproteins/cholesterol in Genomic Instability and Chromosome Mis-segregation in Alzheimer\u27s and Cardiovascular Disease

Several lines of evidence link Alzheimer\u27s disease (AD) to atherosclerosis (CVD), including that elevated low density lipoprotein (LDL)-cholesterol is a common risk factor. Development of genomic instability could also link the two diseases. Previous fluorescence in situ hybridization (FISH) analyses revealed a clonal expansion of aneuploid smooth muscle cells underlying atherosclerotic plaques. Likewise, cellular and mouse models of AD revealed tau-dependent mitotic defects and subsequent aneuploidy partly resulting from amyloid-beta (A&beta) interference with microtubule (MT) stability, and specific MT motors function. Moreover, AD patients develop aneuploid/hyperploid cells in brain and peripheral tissues, implicating similar mechanism that may lead to apoptosis and neurodegeneration. This dissertation tested the hypothesis that elevated lipoproteins and cholesterol may contribute to genomic instability in AD and CVD and showed that: (1) treatment with oxidized LDL (OX-LDL), LDL and water soluble cholesterol, but not high density lipoprotein (HDL), induced chromosome mis-segregation, including trisomy and tetrasomy 12, 21, and 7 in human epithelial cells (hTERT-HME1), primary aortic smooth muscle cells, fibroblasts, mouse splenocytes and neural precursors; (2) LDL-induced aneuploidy may depend on a functional LDL receptor (LDLR), but not amyloid precursor protein (APP) gene; (3) fibroblasts and brain cells of patient with the mutation in the Niemann-Pick C1 gene (NPC1) characterized by impaired intracellular cholesterol trafficking and changed intracellular cholesterol distribution harbored trisomy 21 cells; (4) young wild-type mice fed high and low cholesterol diets developed aneuploidy in spleen but not in brain cells within 12 weeks; (5) like with the studies on A&beta-induced aneuploidy, (Ca2+) chelation reduced OX-LDL and LDL-mediated chromosomal instability; and (6) altering plasma membrane fluidity with ethanol attenuated OX-LDL and LDL-induced aneuploidy. These results suggest a novel biological mechanism by which disrupted cholesterol homeostasis may promote both atherosclerosis and AD by inducing chromosome mis-segregation and development of aneuploid cells. Understanding the cause and consequence of chromosomal instability as a common pathological trait in AD and CVD may be beneficial to designing therapies relevant for both diseases

Mitotic Spindle Defects and Chromosome Mis-Segregation Induced by LDL/Cholesterol—Implications for Niemann-Pick C1, Alzheimer’s Disease, and Atherosclerosis

<div><p>Elevated low-density lipoprotein (LDL)-cholesterol is a risk factor for both Alzheimer’s disease (AD) and Atherosclerosis (CVD), suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy–in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (Aß) inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated Aß, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1) high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis’ first prediction, 2) Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3) oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4) LDL-induced aneuploidy requires the LDL receptor, but not Aß, showing that LDL works differently than Aß, with the same end result, 5) cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6) ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol’s aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol consumption reduces the risk of developing atherosclerosis or AD. These results suggest a novel, cell cycle mechanism by which aberrant cholesterol homeostasis promotes neurodegeneration and atherosclerosis by disrupting chromosome segregation and potentially other aspects of microtubule physiology.</p></div

Characteristics of the Niemann-Pick Type C (NPC) and Control Samples.

<p>yr = year; NK = not known. Human fibroblasts were purchased from Coriell and brains from NICHD Brain and Tissue Bank for Developmental Disorders. Independent T-test revealed no age difference between NPC and control brain donors (20.9±8.6 vs. 17.3±11.1, p = 0.61).</p

Mitotic spindle structure disrupted by cholesterol.

<p>(A) hTERT cells were treated for 24 hr with 4 µg/ml WsCh and the structure of the mitotic spindles observed and analyzed for abnormal DNA localization, lagging chromosomes, super-numerary centrosomes, and dis-arrayed microtubules. There was a significant increase in abnormal mitotic spindle structure induce by cholesterol exposure, with dis-arrayed microtubules and mis-localized DNA being the most prominent defects. (B) Examples of normal spindles in untreated cells and abnormal spindles in cholesterol-treated cells.</p