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Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience‐guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA‐approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)‐like study involving such candidate gerotherapeutics. Geroscience‐guided approaches seek to delay the onset and progression of chronic conditions by targeting the pathways of aging. This approach is likely to improve overall health in old age by addressing aging—the largest risk factor for the leading causes of morbidity. Here, we propose the creation of a standardized process for evaluating FDA‐approved drugs for their geroscience potential, permitting the prioritization of efforts and investments for translating geroscience discoveries.

Differences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22–93 years of age using ATAC-seq, RNA-seq, and flow cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte and cytotoxic cell functions. These changes are greater in magnitude in men and accompanied by a male-specific decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. Impact of age and sex on immune phenotypes can be visualized at https://immune-aging.jax.org to provide insights into future studies. Whether the immune system aging differs between men and women is barely known. Here the authors characterize gene expression, chromatin state and immune subset composition in the blood of healthy humans 22 to 93 years of age, uncovering shared as well as sex-unique alterations, and create a web resource to interactively explore the data.

Higher Red Blood Cell Distribution Width (RDW or anisocytosis) predicts incident coronary artery disease (CAD) plus all-cause and cardiovascular mortality, but its predictive value for other common diseases in healthy volunteers is less clear. We aimed to determine the shorter and longer term associations between RDW and incident common conditions in participants free of baseline disease, followed for 9 years. We undertook a prospective analysis of RDW% using 240,477 healthy UK Biobank study volunteers aged 40-70 years at baseline, with outcomes ascertained during follow-up (≤9 years). Participants were free of anemia, CAD, type-2 diabetes, stroke, hypertension, COPD, and any cancer (except non-melanoma skin cancer) at baseline. Survival models (with competing Hazards) tested associations with outcomes from hospital admission records and death certificates. High RDW (≥15% variation, n = 6,050) compared to low (<12.5% n = 20,844) was strongly associated with mortality (HR 3.10: 95% CI 2.57 to 3.74), adjusted for age, sex, smoking status, education level, mean cell volume and hemoglobin concentration. Higher RDW was also associated with incident CAD (sub-HR 1.67: 1.40 to 1.99), heart failure, peripheral vascular disease, atrial fibrillation, stroke, and cancer (sHR 1.37: 1.21 to 1.55; colorectal cancer sHR 1.92: 1.36 to 2.72), especially leukemia (sHR 2.85: 1.63 to 4.97). Associations showed dose-response relationships, and RDW had long-term predictive value (≥4.5 years after assessment) for the majority of outcomes, which were similar in younger and older persons. In conclusion, higher RDW predicted onsets of a wide range of common conditions as well as mortality in a large healthy volunteer cohort. RDW is not just a short term predictor, as high levels were predictive 4.5 to 9 years after baseline in healthy volunteers. The wide range of outcomes reflects known RDW genetic influences, including diverse disease risks. RDW may be a useful clinical marker for inclusion in wellness assessments.

Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging‐related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40–70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow‐up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate‐adjusted p‐values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92–0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06–1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age‐related health outcomes. Telomere lengthening may offer little gain in later‐life health status and face increasing cancer risks. We estimated associations between measured telomere length (TL) and several aging outcomes by using TL‐associated inherited genetic variants, which are robust to later environmental exposures (confounders)(top X). Genetically determined TL was associated with increased risks of cancers and reduced risks of cardiovascular disease, but little change in other studied age‐related health outcomes. There was genetic evidence consistent with these findings being caused through telomere length itself, rather than through another (unknown) pathway (bottom X).

Despite widespread influenza vaccination programs, influenza remains a major cause of morbidity and mortality in older adults. Age-related changes in multiple aspects of the adaptive immune response to influenza have been well-documented including a decline in antibody responses to influenza vaccination and changes in the cell-mediated response associated with immune senescence. This review will focus on T cell responses to influenza and influenza vaccination in older adults, and how increasing frailty or coexistence of multiple (≥2) chronic conditions contributes to the loss of vaccine effectiveness for the prevention of hospitalization. Further, dysregulation of the production of pro- and anti-inflammatory mediators contributes to a decline in the generation of an effective CD8 T cell response needed to clear influenza virus from the lungs. Current influenza vaccines provide only a weak stimulus to this arm of the adaptive immune response and rely on re-stimulation of CD8 T cell memory related to prior exposure to influenza virus. Efforts to improve vaccine effectiveness in older adults will be fruitless until CD8 responses take center stage.

Detecting multiplets in single nucleus (sn)ATAC-seq data is challenging due to data sparsity and limited dynamic range. AMULET (ATAC-seq MULtiplet Estimation Tool) enumerates regions with greater than two uniquely aligned reads across the genome to effectively detect multiplets. We evaluate the method by generating snATAC-seq data in the human blood and pancreatic islet samples. AMULET has high precision, estimated via donor-based multiplexing, and high recall, estimated via simulated multiplets, compared to alternatives and identifies multiplets most effectively when a certain read depth of 25K median valid reads per nucleus is achieved.

Age-associated dementia and Alzheimer's disease (AD) are currently epidemic. Neither their cause nor connection to the metabolic syndrome (MS) is clear. Suppression of deacetylase survival factor sirtuin 1 (SIRT1), a key host defense, is a central feature of AD. Age-related MS and diabetes are also causally associated with suppressed SIRT1 partly due to oxidant glycotoxins [advanced glycation end products (AGEs)]. Changes in the modern diet include excessive nutrient-bound AGEs, such as neurotoxic methyl-glyoxal derivatives (MG). To determine whether dietary AGEs promote AD, we evaluated WT mice pair-fed three diets throughout life: low-AGE (MG-), MG-supplemented low-AGE (MG+), and regular (Reg) chow. Older MG+-fed mice, similar to old Reg controls, developed MS, increased brain amyloid-β42, deposits of AGEs, gliosis, and cognitive deficits, accompanied by suppressed SIRT1, nicotinamide phosphoribosyltransferase, AGE receptor 1, and PPARγ. These changes were not due to aging or caloric intake, as neither these changes nor the MS were present in age-matched, pair-fed MGmice. The mouse data were enhanced by significant temporal correlations between high circulating AGEs and impaired cognition, as well as insulin sensitivity in older humans, in whom dietary and serum MG levels strongly and inversely associated with SIRT1 gene expression. The data identify a specific AGE (MG) as a modifiable risk factor for AD and MS, possibly acting via suppressed SIRT1 and other host defenses, to promote chronic oxidant stress and inflammation. Because SIRT1 deficiency in humans is both preventable and reversible by AGE reduction, a therapeutic strategy that includes AGE reduction may offer a new strategy to combat the epidemics of AD and MS.

The number of people over the age of 60 is expected to double by 2050 according to the WHO. This emphasizes the need to ensure optimized resilience to health stressors in late life. In older adults, influenza is one of the leading causes of catastrophic disability (defined as the loss of independence in daily living and self-care activities). Influenza vaccination is generally perceived to be less protective in older adults, with some studies suggesting that the humoral immune response to the vaccine is further impaired in cytomegalovirus (CMV)-seropositive older people. CMV is a β-herpes virus infection that is generally asymptomatic in healthy individuals. The majority of older adults possess serum antibodies against the virus indicating latent infection. Age-related changes in T-cell-mediated immunity are augmented by CMV infection and may be associated with more serious complications of influenza infection. This review focuses on the impact of aging and CMV on immune cell function, the response to influenza infection and vaccination, and how the current understanding of aging and CMV can be used to design a more effective influenza vaccine for older adults. It is anticipated that efforts in this field will address the public health need for improved protection against influenza in older adults, particularly with regard to the serious complications leading to loss of independence.

While Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is disrupting lives across the globe for everyone, it has a more devastating impact on the health of older adults, especially that of older men. This pandemic has highlighted the crucial importance of considering an individual’s age and biological sex in the clinic in addition to other confounding diseases (Kuchel, G.A, J Am Geriatr Soc, 67, 203, 2019, Tannenbaum, C., Nature, 575 451-458, 2009) As an interdisciplinary team of scientists in immunology, hematology, genomics, bioinformatics, and geriatrics, we have been studying how age and sex shape the human immune system. Herein we reflect on how our recent findings on the alterations of the immune system in aging might contribute to our current understanding of COVID-19 infection rate and disease risk.

One of the most profound public health consequences of immune senescence is reflected in an increased susceptibility to influenza and other acute respiratory illnesses, as well as a loss of influenza vaccine effectiveness in older people. Common medical conditions and mental and psychosocial health issues as well as degree of frailty and functional dependence accelerate changes associated with immune senescence. All contribute to the increased risk for complications of influenza infection, including pneumonias, heart diseases, and strokes that lead to hospitalization, disability, and death in the over 65 population. Changes in mucosal barrier mechanisms and both innate and adaptive immune functions converge in the reduced response to influenza infection, and lead to a loss of antibody-mediated protection against influenza with age. The interactions of immune senescence and reduced adaptive immune responses, persistent cytomegalovirus infection, inflammaging (chronic elevation of inflammatory cytokines), and dysregulated cytokine production, pose major challenges to the development of vaccines designed to improve T-cell-mediated immunity. In older adults, the goal of vaccination is more realistically targeted to providing clinical protection against disease rather than to inducing sterilizing immunity to infection. Standard assays of antibody titers correlate with protection against influenza illness but do not detect important changes in cellular immune mechanisms that correlate with vaccine-mediated protection against influenza in older people. This article will discuss: (i) the burden of influenza in older adults and how this relates to changes in T-cell function, (ii) age-related changes in different T-cell subsets and immunologic targets for improved influenza vaccine efficacy in older, and (iii) the development of correlates of clinical protection against influenza disease to expedite the process of new vaccine development for the 65 and older population. Ultimately, these efforts will address the public health need for improved protection against influenza in older adults and \"vaccine preventable disability.\"