Epigenetic-based age acceleration in a representative sample of older Americans: Associations with aging-related morbidity and mortality.

Biomarkers developed from DNA methylation (DNAm) data are of growing interest as predictors of health outcomes and mortality in older populations. However, it is unknown how epigenetic aging fits within the context of known socioeconomic and behavioral associations with aging-related health outcomes in a large, population-based, and diverse sample. This study uses data from a representative, panel study of US older adults to examine the relationship between DNAm-based age acceleration measures in the prediction of cross-sectional and longitudinal health outcomes and mortality. We examine whether recent improvements to these scores, using principal component (PC)-based measures designed to remove some of the technical noise and unreliability in measurement, improve the predictive capability of these measures. We also examine how well DNAm-based measures perform against well-known predictors of health outcomes such as demographics, SES, and health behaviors. In our sample, age acceleration calculated using "second and third generation clocks," PhenoAge, GrimAge, and DunedinPACE, is consistently a significant predictor of health outcomes including cross-sectional cognitive dysfunction, functional limitations and chronic conditions assessed 2 y after DNAm measurement, and 4-y mortality. PC-based epigenetic age acceleration measures do not significantly change the relationship of DNAm-based age acceleration measures to health outcomes or mortality compared to earlier versions of these measures. While the usefulness of DNAm-based age acceleration as a predictor of later life health outcomes is quite clear, other factors such as demographics, SES, mental health, and health behaviors remain equally, if not more robust, predictors of later life outcomes.

Senescent Cells: Emerging Targets for Human Aging and Age-Related Diseases.

Aging is a major risk factor for numerous human pathologies, including cardiovascular, metabolic, musculoskeletal, and neurodegenerative conditions and various malignancies. While our understanding of aging is far from complete, recent advances suggest that targeting fundamental aging processes can delay, prevent, or alleviate age-related disorders. Cellular senescence is physiologically beneficial in several contexts, but it has causal roles in multiple chronic diseases. New studies have illustrated the promising feasibility and safety to selectively ablate senescent cells from tissues, a therapeutic modality that holds potential for treating multiple chronic pathologies and extending human healthspan. Here, we review molecular links between cellular senescence and age-associated complications and highlight novel therapeutic avenues that may be exploited to target senescent cells in future geriatric medicine.

Geroscience-Centric Perspective for Geriatric Psychiatry: Integrating Aging Biology With Geriatric Mental Health Research.

The geroscience hypothesis asserts that physiological aging is caused by a small number of biological pathways. Despite the explosion of geroscience research over the past couple of decades, the research on how serious mental illnesses (SMI) affects the biological aging processes is still in its infancy. In this review, we aim to provide a critical appraisal of the emerging literature focusing on how we measure biological aging systematically, and in the brain and how SMIs affect biological aging measures in older adults. We will also review recent developments in the field of cellular senescence and potential targets for interventions for SMIs in older adults, based on the geroscience hypothesis.

Seven knowledge gaps in modern biogerontology.

About a year ago, members of the editorial board of Biogerontology were requested to respond to a query by the editor-in-chief of the journal as to what one question within their field of ageing research still needs to be asked and answered. This editorial is inspired by the wide range and variety of questions, ideas, comments and suggestions received in response to that query. The seven knowledge gaps identified in this article are arranged into three main categories: evolutionary aspects of longevity, biological survival and death aspects, and heterogeneity in the progression and phenotype of ageing. This is not an exhaustive and exclusive list, and may be modified and expanded. Implications of these knowledge gaps, especially in the context of ongoing attempts to develop effective interventions in ageing and longevity are also discussed.

Geroscience: just another name or is there more to it?

The widespread use of the name 'geroscience' in the science of aging is sometimes met with a wary attitude by biogerontologists other than its inventors. Here, we provide an overview of its origin and evolution to assess what exactly it is and to discuss its theoretical and biological relationship to earlier movements of anti-aging medicine and biogerontology more generally. Geroscience posits that targeting aging may offer a cost-effective approach to improve late-life health in humans, and because aging is malleable in model organisms and what regulates this is sufficiently understood, the time is ripe for moving forward to translational and clinical research. The geroscience agenda has rebranded imagery of past traditions, yet the claim that therapies for human aging are ready or within the imminent future is contestable and on brand with tradition, even if biogerontology has made great progress in the past decades.

Introduction: Historical Development and Progression of Clinical Research on Ageing.

Research on ageing has developed since Greek times. It had a very slow advance during the Middle Ages and a big increase in the Renaissance. Darwin contributed somehow to the understanding of the ageing process and initiated a cumulus of ageing explications under the name of Evolutionary Theories. Subsequently, science discovered a great number of genes, molecules, and cell processes that intervened in ageing. This led to the beginning of trials in animals to retard or avoid the ageing process. Alongside this, improvements, geriatric clinical investigations (with the evidence-based medicine tools) started to consolidate as a discipline and commenced to show the challenges and deficiencies of actual clinical trials in ageing; the COVID-19 outbreak revealed some of them. The history of clinical research in ageing has already begun and is essential to affront the challenges that the world will face with the increasing ageing population.

Geroprotector drugs and exercise: friends or foes on healthy longevity?

Physical activity and several pharmacological approaches individually combat age-associated conditions and extend healthy longevity in model systems. It is tantalizing to extrapolate that combining geroprotector drugs with exercise could extend healthy longevity beyond any individual treatment. However, the current dogma suggests that taking leading geroprotector drugs on the same day as exercise may limit several health benefits. Here, we review leading candidate geroprotector drugs and their interactions with exercise and highlight salient gaps in knowledge that need to be addressed to identify if geroprotector drugs can have a harmonious relationship with exercise.

Psychosocial and biological pathways to aging : The role(s) of the behavioral and social sciences in geroscience.

While the biological hallmarks of aging are widely recognized as fundamental mechanisms of biological aging, more recently, there have been calls within geroscience to understand the aging process more comprehensively by adding a perspective of the social hallmarks of aging. Social and behavioral factors, such as socioeconomic status, life events or behavior and beliefs can alter the aging process per se and act in complex interactions with biological pathways. In addition, underlying biological pathways have been proposed for various psychosocial concepts, such as views on age and relationship quality. The aim of the present article is to provide narrative insights into theoretical and empirical developments between social and behavioral gerontology and geroscience or biogerontology. This article focuses on the potential of an interdisciplinary aging research but it also sets out the critical perspective that social gerontology provides.

Transcriptomic analysis reveals a tissue-specific loss of identity during ageing and cancer.

INTRODUCTION: Understanding changes in cell identity in cancer and ageing is of great importance. In this work, we analyzed how gene expression changes in human tissues are associated with tissue specificity during cancer and ageing using transcriptome data from TCGA and GTEx. RESULTS: We found significant downregulation of tissue-specific genes during ageing in 40% of the tissues analyzed, which suggests loss of tissue identity with age. For most cancer types, we have noted a consistent pattern of downregulation in genes that are specific to the tissue from which the tumor originated. Moreover, we observed in cancer an activation of genes not usually expressed in the tissue of origin as well as an upregulation of genes specific to other tissues. These patterns in cancer were associated with patient survival. The age of the patient, however, did not influence these patterns. CONCLUSION: We identified loss of cellular identity in 40% of the tissues analysed during human ageing, and a clear pattern in cancer, where during tumorigenesis cells express genes specific to other organs while suppressing the expression of genes from their original tissue. The loss of cellular identity observed in cancer is associated with prognosis and is not influenced by age, suggesting that it is a crucial stage in carcinogenesis.

Socioeconomic and race/ethnic differences in immunosenescence: Evidence from the Health and Retirement Study.

BACKGROUND: The COVID-19 pandemic has highlighted the urgent need to understand variation in immunosenescence at the population-level. Thus far, population patterns of immunosenescence have not well described. METHODS: We characterized measures of immunosenescence from the 2016 Venous Blood Study from the nationally representative U.S Health and Retirement Study (HRS) of individuals ages 50 years and older. RESULTS: Median values of the CD8+:CD4+, EMRA:Naïve CD4+ and EMRA:Naïve CD8+ ratios were higher among older participants and were lower in those with additional educational attainment. Generally, minoritized race and ethnic groups had immune markers suggestive of a more aged immune profile: Hispanics had a CD8+:CD4+ median value of 0.37 (95 % CI: 0.35, 0.39) compared to 0.30 in non-Hispanic Whites (95 % CI: 0.29, 0.31). Non-Hispanic Blacks had the highest median value of the EMRA:Naïve CD4+ ratio (0.08; 95 % CI: 0.07, 0.09) compared to non-Hispanic Whites (0.03; 95 % CI: 0.028, 0.033). In regression analyses, race/ethnicity and education were associated with large differences in the immune ratio measures after adjustment for age and sex. CONCLUSIONS: Lower educational attainment and minoritized racial ethnic status were associated with higher levels of immunosenescence. This population variation may have important implications for both risk of age-related disease and vulnerability to emerging pathogens (e.g., SARS-CoV-2).

Late-Life Depression is Associated With Increased Levels of GDF-15, a Pro-Aging Mitokine.

OBJECTIVE: In older adults, major depressive disorder (MDD) is associated with accelerated physiological and cognitive aging, generating interest in uncovering biological pathways that may be targetable by interventions. Growth differentiation factor-15 (GDF-15) plays a significant role in biological aging via multiple biological pathways relevant to age and age-related diseases. Elevated levels of GDF-15 correlate with increasing chronological age, decreased telomerase activity, and increased mortality risk in older adults. We sought to evaluate the circulating levels of GDF-15 in older adults with MDD and its association with depression severity, physical comorbidity burden, age of onset of first depressive episode, and cognitive performance. DESIGN: This study assayed circulating levels of GDF-15 in 393 older adults (mean ± SD age 70 ± 6.6 years, male:female ratio 1:1.54), 308 with MDD and 85 non-depressed comparison individuals. RESULTS: After adjusting for confounding variables, depressed older adults had significantly higher GDF-15 serum levels (640.1 ± 501.5 ng/mL) than comparison individuals (431.90 ± 223.35 ng/mL) (t=3.75, d.f.= 391, p=0.0002). Among depressed individuals, those with high GDF-15 had higher levels of comorbid physical illness, lower executive cognitive functioning, and higher likelihood of having late-onset depression. CONCLUSION: Our results suggest that depression in late life is associated with GDF-15, a marker of amplified age-related biological changes. GDF-15 is a novel and potentially targetable biological pathway between depression and accelerated aging, including cognitive aging.

Optimizing preclinical models of ageing for translation to clinical trials.

Preclinical models have been the backbone of translational research for more than a century. Rats and mice are critical models in the preliminary stages of drug testing, both for determining efficacy and ruling out potential human-relevant toxicities. Historically, most preclinical pharmacological studies have used young, relatively healthy, inbred male models in highly controlled environments. In the field of geriatric pharmacology, there is a growing focus on the importance of using more appropriate preclinical models both in the testing of therapeutics commonly used in older populations, and in the evaluation of potential geroprotective drug candidates. Here we provide a commentary on optimizing preclinical models of ageing for translation to clinical trials. We will discuss approaches to modelling clinically relevant contexts such as age, sex, genetic diversity, exposures and environment, as well as measures of clinically relevant outcomes such as frailty and healthspan. We will identify the strengths and limitations of these approaches and areas for improvement. We will also briefly cover new preclinical models that move beyond rodents. We hope this commentary will be a springboard for larger discussions on optimizing preclinical ageing models for testing therapeutics.

Blood Biomarkers for Healthy Aging.

Measuring the abundance of biological molecules and their chemical modifications in blood and tissues has been the cornerstone of research and medical diagnoses for decades. Although the number and variety of molecules that can be measured have expanded exponentially, the blood biomarkers routinely assessed in medical practice remain limited to a few dozen, which have not substantially changed over the last 30-40 years. The discovery of novel biomarkers would allow, for example, risk stratification or monitoring of disease progression or the effectiveness of treatments and interventions, improving clinical practice in myriad ways. In this review, we combine the biomarker discovery concept with geroscience. Geroscience bridges aging research and translation to clinical applications by combining the framework of medical gerontology with high-technology medical research. With the development of geroscience and the rise of blood biomarkers, there has been a paradigm shift from disease prevention and cure to promoting health and healthy aging. New -omic technologies have played a role in the development of blood biomarkers, including epigenetic, proteomic, metabolomic, and lipidomic markers, which have emerged as correlates or predictors of health status, from disease to exceptional health.

Targeting the hallmarks of aging to improve influenza vaccine responses in older adults.

Age-related declines in immune response pose a challenge in combating diseases later in life. Influenza (flu) infection remains a significant burden on older populations and often results in catastrophic disability in those who survive infection. Despite having vaccines designed specifically for older adults, the burden of flu remains high and overall flu vaccine efficacy remains inadequate in this population. Recent geroscience research has highlighted the utility in targeting biological aging to improve multiple age-related declines. Indeed, the response to vaccination is highly coordinated, and diminished responses in older adults are likely not due to a singular deficit, but rather a multitude of age-related declines. In this review we highlight deficits in the aged vaccine responses and potential geroscience guided approaches to overcome these deficits. More specifically, we propose that alternative vaccine platforms and interventions that target the hallmarks of aging, including inflammation, cellular senescence, microbiome disturbances, and mitochondrial dysfunction, may improve vaccine responses and overall immunological resilience in older adults. Elucidating novel interventions and approaches that enhance immunological protection from vaccination is crucial to minimize the disproportionate effect of flu and other infectious diseases on older adults.

The effect of metformin on influenza vaccine responses in nondiabetic older adults: a pilot trial.

BACKGROUND: Aging is associated with progressive declines in immune responses leading to increased risk of severe infection and diminished vaccination responses. Influenza (flu) is a leading killer of older adults despite availability of seasonal vaccines. Geroscience-guided interventions targeting biological aging could offer transformational approaches to reverse broad declines in immune responses with aging. Here, we evaluated effects of metformin, an FDA approved diabetes drug and candidate anti-aging drug, on flu vaccination responses and markers of immunological resilience in a pilot and feasibility double-blinded placebo-controlled study. RESULTS: Healthy older adults (non-diabetic/non-prediabetic, age: 74.4 ± 1.7 years) were randomized to metformin (n = 8, 1500 mg extended release/daily) or placebo (n = 7) treatment for 20 weeks and were vaccinated with high-dose flu vaccine after 10 weeks of treatment. Peripheral blood mononuclear cells (PBMCs), serum, and plasma were collected prior to treatment, immediately prior to vaccination, and 1, 5, and 10 weeks post vaccination. Increased serum antibody titers were observed post vaccination with no significant differences between groups. Metformin treatment led to trending increases in circulating T follicular helper cells post-vaccination. Furthermore, 20 weeks of metformin treatment reduced expression of exhaustion marker CD57 in circulating CD4 T cells. CONCLUSIONS: Pre-vaccination metformin treatment improved some components of flu vaccine responses and reduced some markers of T cell exhaustion without serious adverse events in nondiabetic older adults. Thus, our findings highlight the potential utility of metformin to improve flu vaccine responses and reduce age-related immune exhaustion in older adults, providing improved immunological resilience in nondiabetic older adults.

Healthspan extension, completeness of life and justice.

Recent progress in geroscience holds the promise of significantly slowing down or even reversing ageing and age-related diseases, and thus increasing our healthspans. In this paper, I offer a novel argument in favour of developing such technology and making it unconditionally available to everyone. In particular, I argue that justice requires that each person be provided with sufficient opportunities to have a 'complete life', that many people currently lack such opportunities, and that we would substantially improve the status quo by giving them access to anti-ageing technology.

Fatigue in Alzheimer's disease: biological basis and clinical management-a narrative review.

BACKGROUND: Fatigue is a common symptom in neurodegenerative diseases and is associated with decreased cognitive performances. A full knowledge of the causes and physiopathological pathways leading to fatigue in Alzheimer's disease could help treating this symptom and obtain positive effects on cognitive functions. OBJECTIVES: To provide an overview of the clinical conditions and the biological mechanisms leading to fatigue in Alzheimer's disease patients. To review the recent advances on fatigue management and describe the landscape of future possibilities. METHODS: We performed a narrative review including all type of studies (e.g. cross-sectional and longitudinal analysis, reviews, clinical trials). RESULTS: We found very few studies considering the symptom fatigue in Alzheimer's disease patients. Populations, designs, and objectives varied across studies rendering comparability across studies difficult to perform. Results from cross-sectional and longitudinal analysis suggest that the amyloid cascade may be involved in the pathogenesis of fatigue and that fatigue may be a prodromal manifestation of Alzheimer's disease. Fatigue and neurodegeneration of Alzheimer's disease could share common brain signatures (i.e. hippocampal atrophy and periventricular leukoaraiosis). Some mechanisms of aging (i.e. inflammation, mitochondrial dysfunction, telomere shortening) may be proposed to play a common underlying role in Alzheimer's disease neurodegeneration and muscle fatigability. Considering treatments, donepezil has been found to reduce cognitive fatigue in a 6-week randomized controlled study. Fatigue is frequently reported as an adverse event in patients treated by anti-amyloid agents in clinical trials. CONCLUSION: The literature is actually inconclusive about the main causes of fatigue in Alzheimer's disease individuals and its potential treatments. Further research is needed to disentangle the role of several components such as comorbidities, depressive symptoms, iatrogenic factors, physical decline and neurodegeneration itself. Given the clinical relevance of this symptom, it seems to be important to systematically assess fatigue by validated tools in Alzheimer's disease clinical trials.

Effects of lifespan-extending interventions on cognitive healthspan.

Ageing is known to be the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease. They are currently incurable and worsen over time, which has broad implications in the context of lifespan and healthspan extension. Adding years to life and even to physical health is suboptimal or even insufficient, if cognitive ageing is not adequately improved. In this review, we will examine how interventions that have the potential to extend lifespan in animals affect the brain, and if they would be able to thwart or delay the development of cognitive dysfunction and/or neurodegeneration. These interventions range from lifestyle (caloric restriction, physical exercise and environmental enrichment) through pharmacological (nicotinamide adenine dinucleotide precursors, resveratrol, rapamycin, metformin, spermidine and senolytics) to epigenetic reprogramming. We argue that while many of these interventions have clear potential to improve cognitive health and resilience, large-scale and long-term randomised controlled trials are needed, along with studies utilising washout periods to determine the effects of supplementation cessation, particularly in aged individuals.

Geroscience: the need to address some issues.

The geroscience field hypothesises that it could be possible to delay all age-related diseases by delaying the ageing process itself, and not by curing each age-related disease individually. While this perspective is attracting, some issues provisionally prohibit to fully adhere to it, such as the risk for some over-enthusiasm or scientism and the tendency to accept that results observed in animal models can be easily translated in human beings. Particularly, it is not clear whether geroscience plans to delay or suppress ageing, or if healthspan could become very close to lifespan. This article lists some of these issues, in the hope that supporters of geroscience will grasp them to allow a full development of the field, and argues that geroscience should avoid reductionist approaches not taking into account social and behavioural complex aspects of human ageing.

Hydrogen sulfide in ageing, longevity and disease.

Hydrogen sulfide (H2S) modulates many biological processes, including ageing. Initially considered a hazardous toxic gas, it is now recognised that H2S is produced endogenously across taxa and is a key mediator of processes that promote longevity and improve late-life health. In this review, we consider the key developments in our understanding of this gaseous signalling molecule in the context of health and disease, discuss potential mechanisms through which H2S can influence processes central to ageing and highlight the emergence of novel H2S-based therapeutics. We also consider the major challenges that may potentially hinder the development of such therapies.