Long-term Persistent Organic Pollutants Exposure Induced Telomere Dysfunction and Senescence-Associated Secretary Phenotype

Abstract

Environmentally persistent organic pollutant (POP) is the general term for refractory organic compounds that show long-range atmospheric transport, environmental persistence, and bioaccumulation. It has been reported that the accumulation of POPs could lead to cellular DNA damage and adverse effects of on metabolic health. To better understand the mechanism of the health risks associated with POPs, we conducted an evidence-based cohort investigation (n = 5,955) at the Jinghai e-waste disposal center in China from 2009 to 2016, where people endure serious POP exposure. And high levels of aging-related diseases, including hypertension, diabetes, autoimmune diseases, and reproductive disorders were identified associated with the POP exposure. In the subsequent molecular level study, an increased telomere dysfunction including telomere multiple telomere signals, telomere signal-free ends, telomere shortening and activation of alternative lengthening of telomeres were observed, which might result from the hypomethylated DNA modification induced telomeric repeat-containing RNA overexpression. Moreover, dysfunctional telomere-leaded senescence-associated secretory phenotype was confirmed, as the proinflammatory cytokines and immunosenescence hallmarks including interleukin-6, P16INK4a, and P14ARF were stimulated. Thus, we proposed that the dysfunctional telomere and elevated systemic chronic inflammation contribute to the aging-associated diseases, which were highly developed among the POP exposure individuals.

Chronic inflammation in the etiology of disease across the life span

“…Among the known endogenous causes of this phenotype are DNA damage, dysfunctional telomeres, epigenomic disruption, mitogenic signals and oxidative stress 56 . The non-endogenous contributors are thought to include chronic infections 57 , lifestyle-induced obesity 58 , microbiome dysbiosis 59 , diet 60 , social and cultural changes 61,62 and environmental and industrial toxicants 63 . The fact that differences exist in the extent to which older adults exhibit SCI 52,64 is thought to be indicative of inter-individual differences in exposure to these and other related pro-inflammatory factors, although studies documenting within-person associations between these risk factors and SCI are limited.…”

“…Most prominently, SCI-related disease rates have increased dramatically for both older and younger individuals living in industrialized countries who follow a Western lifestyle but are relatively rare among individuals in non-Westernized populations who adhere to diets, lifestyles and ecological niches that more closely resemble those present during most of human evolution [65][66][67][68][69][70][71] . Furthermore, dietary and lifestyle habits, as well as exposure to a variety of different pollutants, can increase oxidative stress, upregulate mitogenic signaling pathways and cause genomic and epigenomic perturbations 8,60,62,63 that can induce the SASP. Further evidence for a role of lifestyle in the development of chronic inflammation comes from a study of 210 healthy twins between 8 and 82 years old, which found that non-heritable factors are the strongest contributors to differences in chronic inflammation across individuals 72 and that exposure to environmental factors, which have been collectively called the exposome, are the main drivers of SCI.…”

Onchocerciasis Fingerprints in the Geriatric Population: Does Host Immunity Play a Role?

“…Ageing is accompanied by a progressive decline in immune function, referred to as immunosenescence [18,19]. At the cell level, T-cell sub-populations show major changes, resulting in a shift towards a less functional status, with a corresponding decrease in the number of naive T-cells (able to react to new challenges) and an accumulation of terminally differentiated T-cells (only reacting to one specific antigen) and senescent cells [20].…”

“…Indeed, clinical reports indicate that the ability to mount primary immune responses against novel antigens reduces significantly with age [24], leading to a decrease in response to vaccines by elderly individuals [25][26][27] and an increase in their susceptibility to diseases [28][29][30][31]. This situation is further complicated by the aging-related accumulation of senescent T-cells that secrete pro-inflammatory substances and matrixdegrading enzymes [19,32,33], favorable for the development of diseases [34]. Age-related changes in eosinophil functional activity were observed upon the examination of eosinophil degranulation of eosinophil-derived neurotoxins when stimulated with interleukin (IL)-5.…”

Major depression and enhanced molecular senescence abnormalities in young and middle-aged adults

“…SASP changes are dynamic and can occur in response to activated oncogenes, metabolic insults, biological and psychosocial stress, and damage/danger signals. The enhanced secretion of SASP signaling proteins after a deleterious stimuli have been previously associated with the development of canonical hallmarks of cellular aging (e.g., telomere attrition, higher expression of p16 ink4 ); likewise, cellular senescence changes can drive the cellular secretome towards an enhanced SASP profile 20–23 . Under non-pathological circumstances, protective cellular responses are rapidly activated to restore the cellular homeostasis 24 .…”