Current Aging Science - Volume 8, Issue 2, 2015

The number of aged individuals within the global population is increasing, which foreshadows a major societal and global health challenge. By 2050 those over 65 years old will outnumber children under 15 years of age. This situation will bring with it multifarious variations in health and functional status, occurring with increasing age and which remain incompletely understood. Ageing, however, is not solely a passive degenerative process but one that is actively regulated by distinct molecular pathways. Understanding this molecular basis of ageing is an essential step for therapeutic manipulation to combat age-related disease. Diseases such as SSc, RA and SLE may share common age related pathways of early dysregulation with other diseases of ageing, such that the biomarkers and interventions applied to prevent late stage disease will also tackle common fundamental pathways of ageing processes. This chapter will seek to explore and discuss the possible influence of these factors and their impact on disease processes, with specific reference to SSc in the context of it being a disease of ageing. It will address the contribution of socioeconomic, psychosocial and nutritional confounders of health span through the life course. In particular, it will seek to contextualize the development of inflammatory burden and allostatic overload and their contribution to morbidity and mortality. Importantly, this chapter will provide a context for transgenerational and other epigenetic effects, which are emerging as contributory components in disease susceptibility and progression.

Age is the most important risk factor for the development of infectious diseases, cancer and chronic inflammatory diseases including rheumatoid arthritis (RA). The very act of living causes damage to cells. A network of molecular, cellular and physiological maintenance and repair systems creates a buffering capacity against these damages. Aging leads to progressive shrinkage of the buffering capacity and increases vulnerability. In order to better understand the complex mammalian aging processes, nine hallmarks of aging and their interrelatedness were recently put forward. RA is a chronic autoimmune disease affecting the joints. Although RA may develop at a young age, the incidence of RA increases with age. It has been suggested that RA may develop as a consequence of premature aging (immunosenescence) of the immune system. Alternatively, premature aging may be the consequence of the inflammatory state in RA. In an effort to answer this chicken and egg conundrum, we here outline and discuss the nine hallmarks of aging, their contribution to the pre-aged phenotype and the effects of treatment on the reversibility of immunosenescence in RA.

Osteoarthritis (OA) is the most common form of arthritis and a huge health and financial burden. The prevalence and incidence of OA are likely to rise due to increasing life expectancy. Although the link between aging and OA is well established, little is known about the mechanisms by which aging contributes to OA development. In recent years, progress has been made in understanding the molecular mechanisms of chondrocyte aging and senescence. Aging and senescent chondrocytes display a senescence-associated secretory phenotype (SASP) associated with increased secretion of pro-inflammatory mediators, extracellular matrix degrading enzymes and oxidative stress, all of which can contribute to the development and progression of OA. There is also evidence that autophagy, an essential homeostatic process, declines with aging and during OA. This review will focus on our current understanding of chondrocyte aging, senescence, and autophagy and their potential roles in the development and progression of OA. An understanding of these processes would be very useful in devising strategies to treat OA or to delay its development.

The lifespan of humans has increased drastically over the last decades; considerable effort has been applied to delineate the mechanisms behind aging in order to find strategies for longevity. As the benefits of the gained knowledge might extend to diseases, where accelerated aging is suspected, the role of aging in the systemic autoimmune disease Systemic Lupus Erythematosus (SLE) is of particular interest. In this review the immunological similarities of SLE and aging are analyzed on three levels: the clinical, the cellular and the molecular, in order to find possible common pathological mechanisms. Common clinical features (e.g. increased infection rates, incidence of tumors and cardiovascular diseases) of SLE-patients and elderly individuals and shared characteristics of immuno-senescence and SLE are identified. These similarities are strongest in the adaptive immune system, where terminally differentiated T-cells and an immunological risk profile are found in both conditions. Also the aging innate immune system has overlapping features with SLE, exemplified by a generally lowered phagocytic capacity. However, great disparities between the aging immune system and SLE become apparent on a closer look, affecting numbers, phenotype and function of most immune cells, ranging from NETosis by granulocytes to the mechanisms underlying abnormal IL-2 production by T-cells. On the molecular level, also the increased presence of aging mechanisms like telomere attrition, DNA damage, autophagy and the characteristics of the mTOR pathway in SLE, possibly contributing to the shared changes on the cellular and clinical level are elaborated. The possible implications thereof concern existing (hydroxychloroquine, rapamycine, Glucocorticoids) as well as novel therapeutic strategies targeting more specific pathways which might rapidly reach the clinical arena. Overall a differential view on the similarities of aging and SLE and possible consequences is presented.

Chronic pain is highly prevalent in older adults, and until recently, was considered to be common but relatively “benign.” Mounting evidence, however, suggests that some of the 116 million US adults who suffer from chronic pain are also at an increased risk for developing age-related diseases prematurely, suffering earlier cognitive and physical decline, and experiencing earlier mortality. Given the aging US population and the prevalence of chronic pain along with related healthcare consequences, there is a critical need to better understand the relationship between aging and chronic pain. Herein, we focus on one chronic pain state, fibromyalgia, and provide an overview of the evidence suggesting that individuals with this chronic pain condition show signs of premature aging.

Gout is the most common auto-inflammatory arthritis that leads to severe comorbidities such as cardiovascular diseases, renal impairment and metabolic disorders at an early age. We hypothesize that chronic as well as frequent flares of intermittent inflammation, caused by uric acid contribute to an early onset of cardiovascular-, renal- and metabolic diseases. Persistent exposure of the cells to such inflammatory events elaborates DNA damage, excessive cell turnover inconsistent with age and telomere shortening which is representative for accelerated senescence. In this review we aim to untangle the intriguing effect of inflammation-induced cellular senescence on the high prevalence of age-related cardiovascular, renal and metabolic diseases in gout.

Sicca complaints (sensation of dry mouth and/or eyes) are present in about a quarter of the individuals above the age of 65 years old and are mainly due to medication. However, physiological changes that occur during aging might also lead to a diminished glandular function. These age-related changes are, at least in part, to be the consequence of decreased androgen levels. In addition to these physiological effects that occur during normal aging, sicca complaints can also be caused by Sjögren’s syndrome (SS): a systemic auto-inflammatory disorder mainly affecting exocrine glands. Genetic factors, lowered levels of gonadal hormones and (viral) infections appear to contribute to the etiology of the syndrome. The incidence of SS is higher among aged individuals, which might be due to earlier diagnosis, as the onset of SS in an individual with age-related exocrine gland dysfunction lowers the threshold for sicca complaints. On the other hand, physiological aging might be considered as a risk factor for development of SS, resulting in a faster development of the syndrome. Differentiating physiological sicca complaints from SS in the elderly can be challenging, since apparently healthy individuals might present with auto-antibodies and lymphocytic infiltrates in salivary glands might be present as well. The drop in the level of androgens and estrogens upon aging, immunosenescence and pro-inflammatory features of the aging immune system may all contribute to the etiology of pSS in the elderly. In this review, we describe the physiological effects of aging and the influence of SS on exocrine gland morphology and function.