COVID-19 and Crosstalk With the Hallmarks of Aging Salimi, Shabnam; Hamlyn, John M
The journals of gerontology. Series A, Biological sciences and medical sciences,
09/2020, Letnik:
75, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Abstract
Within the past several decades, the emergence of new viral diseases with severe health complications and mortality is evidence of an age-dependent, compromised bodily response to abrupt ...stress with concomitantly reduced immunity. The new severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, causes coronavirus disease 2019 (COVID-19). It has increased morbidity and mortality in persons with underlying chronic diseases and those with a compromised immune system regardless of age and in older adults who are more likely to have these conditions. While SARS-CoV-2 is highly virulent, there is variability in the severity of the disease and its complications in humans. Severe pneumonia, acute respiratory distress syndrome, lung fibrosis, cardiovascular events, acute kidney injury, stroke, hospitalization, and mortality have been reported that result from pathogen–host interactions. Hallmarks of aging, interacting with one another, have been proposed to influence health span in older adults, possibly via mechanisms regulating the immune system. Here, we review the potential roles of the hallmarks of aging, coupled with host–coronavirus interactions. Of these hallmarks, we focused on those that directly or indirectly interact with viral infections, including immunosenescence, inflammation and inflammasomes, adaptive immunosenescence, genomic instability, mitochondrial dysfunction, epigenetic alterations, telomere attrition, and impaired autophagy. These hallmarks likely contribute to the increased pathophysiological responses to SARS-CoV-2 among older adults and may play roles as an additive risk of accelerated biological aging even after recovery. We also briefly discuss the role of antiaging drug candidates that require paramount attention in COVID-19 research.
The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic ...diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well‐established clinical guidelines. Physicians are often forced to engage in cycles of “trial and error” that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are “aging faster” to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.
Finding a reference metric for the rate of biological aging is key to understanding the molecular nature of the aging process. Defining and validating this metric in humans opens the door to a new kind of medicine that will overcome the limitation of current disease definitions. We will then be able to approach health in a global perspective and bring life course preventative measures to the center of attention.
Objectives
To examine the hypothesis that the inflammatory state of aging is a risk factor for accelerated renal function (RF) decline using inflammatory biomarkers and RF measures collected over 9 ...years of follow‐up in relatively healthy individuals enrolled in the Invecchiare in Chianti study.
Design
Longitudinal.
Setting
Community.
Participants
Individuals aged 60 and older with baseline estimated glomerular filtration rate (eGFR) of 60 mL/min per 1.73 m2 and greater and no diabetes mellitus (DM) (N = 687).
Measures
eGFR, as a proxy for RF, was determined using the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation at baseline and 3‐, 6‐, and 9‐year follow‐up. Incident chronic kidney disease (CKD) was defined as new‐onset eGFR less than 60 mL/min per 1.73 m2 at each follow‐up. Predictors included baseline and time‐dependent inflammatory biomarkers: soluble tumor necrosis factor alpha receptors (sTNFα‐R1 and ‐R2), interleukin (IL)‐6, IL‐18, IL‐1β, IL‐1 receptor antagonist, and high‐sensitivity C‐reactive protein.
Results
Higher baseline sTNFα‐R1 was significantly associated with lower eGFR over 9 years, independent of DM or blood pressure (baseline: β^ = −0.39, P = .001; 3‐year: β^ = −0.26, P = .001; 6‐year: β^ = −0.36, P = .001; 9‐year: β^ = −0.47, P = .001). The rate of TNFα‐R1 change was significantly associated with rate of eGFR change (β^ = −0.18, P = .001). Baseline sTNFα‐R1 predicted incident CKD (per 1‐standard deviation increment: 3‐year: relative risk (RR) = 1.3, 95% confidence interval (CI) = 1.1–1.5; 6‐year: RR = 1.5, 95% CI = 1.1–2.2; 9‐year RR = 1.6, 95% CI = 1.1–2.2). Similar results were found for sTNFα‐R2.
Conclusion
Baseline TNFα‐R levels and their rates of change were significantly associated with RF decline and incident CKD in older adults independent of DM or blood pressure.
Abstract The recovery after traumatic brain injury (TBI) is hampered by the poor regenerative capacity of the brain. Today there is no treatment available that effectively restores lost brain tissue, ...but much research is focused on the stimulation of endogenous neural stem cells to viably and functionally repopulate the injured parenchyma. It is crucial that the therapies have a proven long-term effect on both regeneration and functional recovery to be clinically interesting. Here we have studied the induction of stem cell activation in rats at three weeks and six weeks after inducing TBI using controlled cortical impact model at a severe setting. We combined intracerebroventricular growth factor and scaffold treatment in order to accomplish an optimal effect on the stem cell regeneration. Immediately after TBI epidermal growth factor infusion with osmotic minipumps was started and continued for seven days. The pumps were removed and an extracellular matrix scaffold containing vascular endothelial growth factor was deposited into the cortical cavity. Three weeks after injury there was a positive effect of the treatment with a significant increase in neuronal and astrocytic regeneration. However, after six weeks there was no difference in the number of newly generated neurons and astrocytes in treated or untreated rats. Evaluation of tissue loss and spatial learning in the Morris water maze corroborated that the treatment had no effect at the later time point. Our results highlight the importance of long-term studies to ensure that a promising effect on tissue regeneration and functional outcome is not only temporary.
Diabetic nephropathy (DN) has become the single leading cause of ESRD in developed nations. Bearing in mind the paucity of effective treatment for DN and progressive CKD, novel targets for treatment ...are sorely needed. We previously reported that increased activity of tonicity-responsive enhancer-binding protein (TonEBP) in monocytes was associated with early DN in humans. We now extend these findings by testing the hypotheses that TonEBP in macrophages promotes hyperglycemia-mediated proinflammatory activation and chronic renal inflammation leading to DN and CKD, and TonEBP genetic variability in humans is associated with inflammatory, renal, and vascular function-related phenotypes. In a mouse model of DN, compared with the wild-type phenotype, TonEBP haplodeficiency associated with reduced activation of macrophages by hyperglycemia, fewer macrophages in the kidney, lower renal expression of proinflammatory genes, and attenuated DN. Furthermore, in a cohort of healthy humans, genetic variants within TonEBP associated with renal function, BP, and systemic inflammation. One of the genetic variants associated with renal function was replicated in a large population-based cohort. These findings suggest that TonEBP is a promising target for minimizing diabetes- and stress-induced inflammation and renovascular injury.
Abstract Introduction This study examines the relationship between postpartum depression (PPD) and cigarette smoking from prior to pregnancy to postpartum. Methods The study sample consisted of ...29,654 U.S. women who reported smoking in the 3 months prior to pregnancy and for whom data on PPD were available from the Pregnancy Risk Assessment Monitoring System (PRAMS). Two sets of analyses were conducted. The first compared smoking at 2 time points (prior to pregnancy and postpartum) and the second at 3 time points (prior to pregnancy, during pregnancy, and postpartum). PPD was defined as responses of “often” or “always” to 2 questions: "Since your baby was born, how often have you felt down, depressed, or sad?" and “Since your new baby was born, how often have you had little interest or little pleasure in doing things?” Results Overall, 22% of the sample endorsed PPD symptoms. In the 2 time-point analysis, controlling for known confounders, participants whose smoking was reduced or unchanged postpartum were about 30% more likely to have PPD compared to those who quit (OR: 1.34; 95% CI = 1.10–1.60, p = 0.001; OR:1.32; 95% CI: 1.10–1.50, p < 0.001 respectively). Participants who increased smoking postpartum were 80% more likely to have PPD compared those who quit (OR: 1.80; 95% CI: 1.50–2.30, p < 0.001). In the 3 time-point analysis, participants who continued smoking at any level during pregnancy and postpartum had 1.48 times the odds of reporting PPD (95% CI: 1.26, 1.73) compared to those who quit during pregnancy and remained quit postpartum. Participants who quit during pregnancy but resumed postpartum had 1.28 times the odds of reporting PPD (95% CI: 1.06, 1.53) compared to those who quit during pregnancy and remained quit postpartum. Conclusion Results suggest an association among women who smoke cigarettes prior to pregnancy between PPD and continued smoking during pregnancy and postpartum.
Atmospheric particulate matter (PM) has been associated with endothelial dysfunction, an early marker of cardiovascular risk. Our aim was to extend this research to a genetically homogenous, ...geographically stable rural population using location-specific moving-average air pollution exposure estimates indexed to the date of endothelial function measurement.
We measured endothelial function using brachial artery flow-mediated dilation (FMD) in 615 community-dwelling healthy Amish participants. Exposures to PM < 2.5 μm (PM
) and PM < 10 μm (PM
) were estimated at participants' residential addresses using previously developed geographic information system-based spatio-temporal models and normalized. Associations between PM exposures and FMD were evaluated using linear mixed-effects regression models, and polynomial distributed lag (PDL) models followed by Bayesian model averaging (BMA) were used to assess response to delayed effects occurring across multiple months.
Exposure to PM
was consistently inversely associated with FMD, with the strongest (most negative) association for a 12-month moving average (- 0.09; 95% CI: - 0.15, - 0.03). Associations with PM
were also strongest for a 12-month moving average but were weaker than for PM
(- 0.07; 95% CI: - 0.13, - 0.09). Associations of PM
and PM
with FMD were somewhat stronger in men than in women, particularly for PM
.
Using location-specific moving-average air pollution exposure estimates, we have shown that 12-month moving-average estimates of PM
and PM
exposure are associated with impaired endothelial function in a rural population.
Wnt1-inducible signaling pathway protein-1 (WISP1) is a novel target of the Wnt pathway for modulating osteogenesis and improving bone strength. However, it is not clear if genetic variants in the ...WISP1 region are associated with bone mineral density (BMD) in human. The aim of this study is to investigate the role of genetic variation in WISP1 gene as a determinant of BMD in 1,510 Old Order Amish (OOA). We performed regional association analysis of 58 tag variants within 5 kb upstream and downstream to WISP1 with BMD and found 5 variants that were associated with BMD at multiple skeletal sites (P values from 2.89 × 10
to 1.62 × 10
), with some significant associations even after adjustment for multiple comparisons. To replicate these results in an independent dataset, we performed a look-up of BMD associations with these variants in European ancestry subjects from the large GEFOS Consortium and observed the nominal associations of two of these variants with BMD (P values: 0.031 to 0.048). In conclusion, we have demonstrated that genetic variants surrounding WISP1 are associated with BMD at multiple skeletal sites in the OOA, thus influencing osteoporosis risk. These results support a role for the WISP1 gene on influencing variation in BMD.
Leukocytosis is a powerful predictor of incident chronic kidney disease (CKD) and related outcomes. However, the association between periodontitis measures and increased leukocytosis in the context ...of CKD has not been well described. We sought to identify which individual measures of periodontal disease may best associate with reduced estimated glomerular filtration rate (eGFR) and albuminuria, and to test if these measures were associated with increased leukocytosis in subjects with established CKD.
We estimated, among 13,270 participants in the National Health and Nutrition Examination Survey III study, the associations between case-based definition of periodontitis, clinical attachment loss (CAL) and pocket depth (PD) as individual measures of periodontal disease, with renal function measures and leukocytosis.
In adjusted multivariate analyses, case-based definition of severe periodontitis was associated with albuminuria (β = 0.003, p = 0.01) but not with eGFR. However, CAL and PD were all individually associated with both albuminuria (β = 0.08, p < 0.001 and β = 0.06, p < 0.001, respectively) and eGFR (β = -0.05, p < 0.001 and β = -0.03, p < 0.001, respectively). We found significant associations between elevated CAL and PD with leukocytosis. Lastly, we found a marked association between the joint presence of CKD and elevated CAL or PD with leukocytosis (odds ratio (OR) 3.3, 95% confidence interval (CI) 1.4-7.5 and OR 3.2, 95% CI 1.1-9.7, respectively).
Individual measures of periodontal disease are associated with renal function and heightened leukocytosis in CKD subjects. The significantly added inflammatory burden noted in CKD subjects with periodontal disease argue for targeting periodontitis treatment as part of our multifaceted approach to CKD patients.
Abstract
It is likely that the dimension and the scope of stress perception are different in different body systems conditioning their specific rates of aging. Moreover, in addition to ...between-individual variabilities in body response to stress, there is inter-organs variability in adaptations resulting in pleiotropy of phenotypes evolved with aging. Epigenetic measures may be considered possible readouts of the extent and proxy of the adaptive response to intrinsic and/or extrinsic stress in body organs. It is thus important to disentangle the epigenetic basis of stress, adaptation, and pathology. In this symposium we discuss a combination of the specific DNA methylation patterns relate to the diseases as an intrinsic stressor and adaptation responses imposed to bodily systems, and also accelerated body organ morbidities. We explain the static and dynamic DNA methylation differentiation over time as the “epigenetic code” of accelerated pathology across various age using longitudinal data.
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