The Role of Epigenetics in Aging and Autoimmunity

The decline in immunocompetence with age is accompanied by the increase in the incidence of autoimmune diseases. Aging of the immune system, or immunosenescence, is characterized by a decline of both T and B cell function, and paradoxically the presence of low-grade chronic inflammation. There is growing evidence that epigenetics, the study of inherited changes in gene expression that are not encoded by the DNA sequence itself, changes with aging. Interestingly, emerging evidence suggests a key role for epigenetics in human pathologies, including inflammatory and neoplastic disorders. Here, we will review the potential mechanisms that contribute to the increase in autoimmune responses in aging. In particular, we will discuss how epigenetic alterations, especially DNA methylation and histone acetylation, are accumulated during aging and how these events contribute to autoimmunity risk.     

Cardiovascular determinants of life span

The prevalence of cardiovascular diseases rises with aging and is one of the main causes of mortality in western countries. In view of the progressively aging population, there is an urge for a better understanding of age-associated cardiovascular diseases and its underlying molecular mechanisms. The risk factors for cardiovascular diseases include unhealthy diet, diabetes, obesity, smoking, alcohol consumption, physical inactivity, and aging. Increased production of oxygen-derived free radicals plays an important role in mediating cardiovascular diseases. Oxidative stress affects the availability and/or balance of key-regulators of vascular homeostasis and favors the development of cardiovascular diseases. Reactive oxygen species are generated by different intracellular molecular pathways principally located in the cytoplasm and in the mitochondria. The mitochondrial protein p66Shc and the deacetylase enzyme SIRT1 were shown to be involved in different aspects of cardiovascular diseases. This review focuses on the latest scientific advances in understanding cardiovascular diseases associated to aging, as well as delineating the possible therapeutic implications of p66Shc and SIRT 1 in this process.     

Epidemiology of the arterial stiffness.

Aortic stiffening is as much an important risk factor in cardiovascular morbidity and mortality, as it serves as reliable surrogate marker for clinical endpoints like myocardial and cerebrovascular incidents. Elevated aortic stiffness induces high systolic blood pressure, augmented pulse pressure with increased ventricular afterload, reduced subendocardial blood flow and augmented pulsatile stress in the peripheral arteries. Factors with relevant impact on the epidemiology of arterial stiffness are widely spread. 3 major groups of parameters influencing the stiffness of the aorta and the large arteries have been studied and described up to now: (i) physiological properties like age, gender, body height, pressure, hormonal state, genetic factors; (ii) environmental factors like nutrition (fish-, salt-, garlic consumption), smoking, performance of sports and aerobic capacity; (iii) diseases like hypertension, hypercholesterolemia, diabetes, coronary heart disease, cerebrovascular disease, renal failure, Marfan-syndrome, growth hormone deficiency. Close association between several of these factors impedes analyzing them independently from each other. Age and blood pressure were found to be the most prominent predictors of arterial stiffness in normal as well as in disease populations. Physiological and environmental factors can modulate these effects of aging, diseases generally seem to amplify them.     

Immunosenescence and inflammaging in the aging process: age-related diseases or longevity?

During aging the immune system (IS) undergoes remarkable changes that collectively are known as immunosenescence. It is a multifactorial and dynamic phenomenon that affects both natural and acquired immunity and plays a critical role in most chronic diseases in older people. For a long time, immunosenescence has been considered detrimental because it may lead to a low-grade, sterile chronic inflammation we proposed to call "inflammaging" and a progressive reduction in the ability to trigger effective antibody and cellular responses against infections and vaccinations. Recently, many scientists revised this negative meaning because it can be considered an essential adaptation/remodeling resulting from the lifelong immunological biography of single individuals from an evolutionary perspective. Inflammaging can be considered an adaptive process because it can trigger an anti-inflammatory response to counteract the age-related pro-inflammatory environment. Centenarians represent a valuable model to study the beneficial changes occurring in the IS with age. These extraordinary individuals reached the extreme limits of human life by slowing down the aging process and, in most cases, delaying, avoiding or surviving the major age-associated diseases. They indeed show a complex and heterogeneous phenotype determined by an improved ability to adapt and remodel in response to harmful stimuli. This review aims to point out the intimate relationship between immunosenescence and inflammaging and how these processes impact unsuccessful aging rather than longevity. We also describe the gut microbiota age-related changes as one of the significant triggers of inflammaging and the sex/gender differences in the immune system of the elderly, contributing to the sex/gender disparity in terms of epidemiology, pathophysiology, symptoms and severity of age-related diseases. Finally, we discuss how these phenomena could influence the susceptibility to COVID-19 infection.     

What age trajectories of cumulative deficits and medical costs tell us about individual aging and mortality risk: Findings from the NLTCS-Medicare data

An important feature of aging-related deterioration in human health is the decline in organisms' resistance to stresses, which contributes to an increase in morbidity and mortality risks. In human longitudinal studies of aging, such a decline is not measured directly, so indirect methods of statistical modeling have to be used for evaluating this characteristic. Since medical interventions reflect severity of occurring health disorders, data from Medicare service use files can be used for such modeling. In this paper, we use the National Long Term Care Survey (NLTCS) data merged with the Medicare service use files to investigate dynamics of stress resistance in the U.S. elderly. We constructed individual indices of cumulative deficits and medical costs and investigated their separate and joint effects on dynamics of mortality risks using the quadratic hazard model (QHM). We found that males show a faster decline in stress resistance with age than females.     

Drivers of age-related inflammation and strategies for healthspan extension

Aging is the greatest risk factor for the development of chronic diseases such as arthritis, type 2 diabetes, cardiovascular disease, kidney disease, Alzheimer's disease, macular degeneration, frailty, and certain forms of cancers. It is widely regarded that chronic inflammation may be a common link in all these age-related diseases. This raises the question, can one alter the course of aging and potentially slow the development of all chronic diseases by manipulating the mechanisms that cause age-related inflammation? Emerging evidence suggests that pro-inflammatory cytokines interleukin-1 (IL-1) and IL-18 show an age-dependent regulation implicating inflammasome-mediated caspase-1 activation in the aging process. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome controls the caspase-1 activation in myeloid-lineage cells in several organs during aging. The NLRP3 inflammasome is especially relevant to aging as it can get activated in response to structurally diverse damage-associated molecular patterns (DAMPs) such as extracellular ATP, excess glucose, ceramides, amyloids, urate, and cholesterol crystals, all of which increase with age. Interestingly, reduction in NLRP3-mediated inflammation prevents age-related insulin resistance, bone loss, cognitive decline, and frailty. NLRP3 is a major driver of age-related inflammation and therefore dietary or pharmacological approaches to lower aberrant inflammasome activation holds promise in reducing multiple chronic diseases of age and may enhance healthspan.     

Are microRNAs true sensors of ageing and cellular senescence?

All living beings are programmed to death due to aging and age-related processes. Aging is a normal process of every living species. While all cells are inevitably progressing towards death, many disease processes accelerate the aging process, leading to senescence. Pathologies such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s disease, cardiovascular disease, cancer, and skin diseases have been associated with deregulated aging. Healthy aging can delay onset of all age-related diseases. Genetics and epigenetics are reported to play large roles in accelerating and/or delaying the onset of age-related diseases. Cellular mechanisms of aging and age-related diseases are not completely understood. However, recent molecular biology discoveries have revealed that microRNAs (miRNAs) are potential sensors of aging and cellular senescence. Due to miRNAs capability to bind to the 3′ untranslated region (UTR) of mRNA of specific genes, miRNAs can prevent the translation of specific genes. The purpose of our article is to highlight recent advancements in miRNAs and their involvement in cellular changes in aging and senescence. Our article discusses the current understanding of cellular senescence, its interplay with miRNAs regulation, and how they both contribute to disease processes.     

The role of melatonin and serotonin in aging

The hypothesis presented in this paper defines aging as a pathological process originating in the pineal gland. This results in a diminished output of melatonin, along with a diminished melatonin to serotonin ratio, leading to a decline in adaptive processes and a predictable syndrome manifested by the "diseases of the aged" (DOA) and subsequent death of the organism. That is, aging is a syndrome of relative melatonin deficiency resulting from the gradual failure of the pineal gland.     

Age-dependent alterations in the structurally determined vascular resistance,pre- to postglomerular resistance ratio and glomerular filtration capacity in kidneys,as studied in aging normotensive rats and spontaneously hypertensive rats

Maximally dilated renal vascular beds of 13-month-old NCR and SHR were compared to explore how aging respectively longstanding primary hypertension structurally alters total renal resistance, pre-/postglomerular resistance ratio and maximal glomerular filtration capacity, as measured per unit kidney weight. According to comparisons of 1.5- and 3.5-month-old NCR and SHR (Folkow et al. 1977). a structurally increased pre-/postglomerular resistance ratio rapidly resets the renal “longterm barostat function” in SHR to match the 30–40% pressure rise, thereby increasing total renal resistance 15–20%, while filtration capacity is unaltered so far. In NCR aging to 13 months hardly alters arterial pressure, but increases total renal resistance 10–15%, mainly affecting postglomerular vessels, while filtration capacity is reduced 25%. 13-month-old SHR show an additional 15% pressure rise and–relative to agematched NCR–a further 35% reduction of filtration capacity with a 30–35% increase of total renal resistance, which mainly affects the postglomerular vessels as the resistance ratio is now barely above that in NCR. Thus, advancing SHR hypertension seems to start a renal vicious circle, because accentuated reductions of filtration capacity are parallelled by structural postglomerular resistance increases, apparently to maintain GFR by raised filtration pressure which, however, accelerates glomerular deterioration.     

Old mice express a transient early resistance to pulmonary tuberculosis that is mediated by CD8 T cells

During the natural aging process the immune system undergoes many alterations. In particular, both the CD4 and CD8 T-cell compartments become compromised, and these changes have serious implications for the capacity of the elderly to control infection. As a result, the elderly are more susceptible to many infectious diseases, including primary infection and reactivation of latent infections. In this study we addressed the capacity of old mice to control an infection with Mycobacterium tuberculosis and to characterize the mechanism by which old mice, paradoxically, can express a transient early resistance to infection. This resistance was shown to be associated with the presence of CD8 T cells within the lungs that were capable of secreting gamma interferon, as illustrated by the demonstration that early resistance was lost in aged CD8 gene-disrupted mice. These studies therefore show that, despite a documented decline in general CD8 T-cell responsiveness in the elderly, a subset of CD8 T cells is an important early mediator of protection in the lungs of old mice that have been infected with M. tuberculosis.     

Hippuric acid: Could became a barometer for frailty and geriatric syndromes?

Aging is a natural biological event that has some downsides such as increased frailty, decline in cognitive and physical functions leading to chronical diseases, and lower quality of life. There is therefore a pressing need of reliable biomarkers to identify populations at risk of developing age-associated syndromes in order to improve their quality of life, promote healthy ageing and a more appropriate clinical management, when needed. Here we discuss the importance of hippuric acid, an endogenous co-metabolite, as a possible hallmark of human aging and age-related diseases, summarizing the scientific literature over the last years. Hippuric acid, the glycine conjugate of benzoic acid, derives from the catabolism by means of intestinal microflora of dietary polyphenols found in plant-based foods (e.g. fruits, vegetables, tea and coffee). In healthy conditions hippuric acid levels in blood and/or urine rise significantly during aging while its excretion drops in conditions related with aging, including cognitive impairments, rheumatic diseases, sarcopenia and hypomobility. This literature highlights the utility of hippuric acid in urine and plasma as a plausible hallmark of frailty, related to low fruit and vegetable intake and changes in gut microflora.     

Evolutionary,biosocial, and cross-cultural perspectives on the variability in human biological aging

Because of our traditional emphasis on evolutionary processes and the causes of variability, human biologists have contributed to the understanding of variability in human biological aging. The shared interests of human characterized by increased phenotypic variation in later stages of life and by reduced adaptive capacity. The papers in this issue illustrate the unique blend of evolutionary, biosocial, and cross-cultural perspectives used by human biologists to study the variation in biological aging. The papers present examples of common methodological paradigms such as theoretical/mathematical models, epidemiological studies, natural experiments, and studies of isolated foci of diseases. The principles of human adaptability and the premises of the life-course perspective may provide the foundation for a conceptual framework that integrates the study of biological, behavioral, and social aspects of human aging. Human biologists can play an important role in refining the theoretical and methodological tools that will be needed to understand the variability in human aging in populations throughout the world.     

Telomerase activation: A potential key modulator for human healthspan and longevity

The elderly population is increasing progressively. Along with this increase the number of age related diseases, such as cardiovascular, neurodegenerative diseases, metabolic impairment and cancer, is also on the rise thereby negatively impacting the burden on health care systems. Telomere shortening and dysfunction results in cellular senescence, an irreversible proliferative arrest that has been suggested to promote organismal aging and disabling age-related diseases. Given that telomerase, the enzyme responsible for maintaining telomere lengths, is not expressed at levels sufficient to prevent telomere shortening in most of our cells, telomeres progressively erode with advancing age. Telomerase activation, therefore, might serve as a viable therapeutic strategy to delay the onset of cellular senescence, tissue dysfunction and organismal decline. Here we analyze the more recent findings in telomerase activation as a potential key modulator for human healthspan and longevity.     

Possible acceleration of aging by adjuvant chemotherapy: A cause of early onset frailty?

Cancer chemotherapy has three main applications. It is curative for a small number of malignancies including childhood leukemia, Hodgkin's and non-Hodgkin's lymphoma, and germ cell malignancies. It has a palliative role for most metastatic epithelial malignancies. Finally, it has an adjuvant role in several types of resected epithelial malignancies particularly breast cancer. First successfully employed in the mid 1970s, adjuvant chemotherapy is associated with up to a 30% relative improvement in long-term overall survival in high risk breast cancer but demonstrates significantly less absolute improvement. Now that adjuvant chemotherapy is being used in lower risk disease, both the relative and absolute improvement in overall survival is even less impressive. With a growing number of long-term survivors, we are only now able to define the delayed implications of adjuvant chemotherapy. These long-term side effects include acceleration of neurocognitive decline, musculoskeletal complications such as early onset osteoporosis, premature skin and ocular changes and the most common long-term complaint; mild to profound fatigue. This complex of problems is suggestive of early onset frailty. This paper explores various potential mechanisms of aging including accumulation of free-radical damage, accumulation of DNA damage, telomere shortening with accompanying decline in telomerase activity and finally a decline in neuroendocrine/immune function. The impact of chemotherapy, particularly those agents used in the adjuvant setting, in relationship to these aging mechanisms is explored. There is good evidence that chemotherapy can effect all these aging mechanisms leading to early onset frailty. The implications of this hypothesis are quite profound. Whereas short-term toxicity of chemotherapy can usually be considered acceptable even for a small improvement in survival, long-term toxicity such as early onset frailty can have an impact on quality of life that could last for years. This possible effect on aging could have implications on the decision to take adjuvant chemo, what agents to use, means to minimize the aging effect and the need to monitor for early onset frailty.     

Regulation of longevity by FGF21: Interaction between energy metabolism and stress responses

Fibroblast growth factor 21 (FGF21) is a hormone-like member of FGF family which controls metabolic multiorgan crosstalk enhancing energy expenditure through glucose and lipid metabolism. In addition, FGF21 acts as a stress hormone induced by endoplasmic reticulum stress and dysfunctions of mitochondria and autophagy in several tissues. FGF21 also controls stress responses and metabolism by modulating the functions of somatotropic axis and hypothalamic-pituitary-adrenal (HPA) pathway. FGF21 is a potent longevity factor coordinating interactions between energy metabolism and stress responses. Recent studies have revealed that FGF21 treatment can alleviate many age-related metabolic disorders, e.g. atherosclerosis, obesity, type 2 diabetes, and some cardiovascular diseases. In addition, transgenic mice overexpressing FGF21 have an extended lifespan. However, chronic metabolic and stress-related disorders involving inflammatory responses can provoke FGF21 resistance and thus disturb healthy aging process. First, we will describe the role of FGF21 in interorgan energy metabolism and explain how its functions as a stress hormone can improve healthspan. Next, we will examine both the induction of FGF21 expression via the integrated stress response and the molecular mechanism through which FGF21 enhances healthy aging. Finally, we postulate that FGF21 resistance, similarly to insulin resistance, jeopardizes human healthspan and accelerates the aging process.     

The effects of aging on dopaminergic neurotransmission: a microPET study of [11C]-raclopride binding in the aged rodent brain

Rodent models are frequently used in aging research to investigate biochemical age effects and aid in the development of therapies for pathological and non-pathological age-related degenerative processes. In order to validate the use of animal models in aging research and pave the way for longitudinal intervention-based animal studies, the consistency of cerebral aging processes across species needs to be evaluated. The dopaminergic system seems particularly susceptible to the aging process, and one of the most consistent findings in human brain aging research is a decline in striatal D2-like receptor (D2R) availability, quantifiable by positron emission tomography (PET) imaging. In this study, we aimed to assess whether similar age effects can be discerned in rat brains, using in vivo molecular imaging with the radioactive compound [(11)C]-raclopride. We observed a robust decline in striatal [(11)C]-raclopride uptake in the aged rats in comparison to the young control group, comprising a 41% decrement in striatal binding potential. In accordance with human studies, these results indicate that substantial reductions in D2R availability can be measured in the aged striatal complex. Our findings suggest that rat and human brains exhibit similar biochemical alterations with age in the striatal dopaminergic system, providing support for the pertinence of rodent models in aging research.     

Autoimmune diseases and reproductive aging

As the population ages, more individuals with autoimmune diseases are experiencing reproductive senescence. Understanding the impact of menopause and age-related androgen decline on disease onset and course, as well as the potential for hormonal interventions, is critically important. In men, lupus erythematosis (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS) are associated with lower androgen levels. However, the impact of age-related declines in testosterone, as well as of testosterone replacement, on disease course remains underexplored. In women, the course of all three diseases with onset after the age of menopause differs from that with onset before menopause. Early age at menopause is associated with increased disease risk, and after menopause, disease course changes in SLE and RA. Less is known about MS. This article summarizes what is known about the relationship between reproductive aging and autoimmune diseases in men and women, and highlights areas for further investigation.