scholarly journals Associations Between a New Biomarker of Elevated Chronic Inflammation and Accelerated Aging

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 141-142
Author(s):  
Line Rasmussen ◽  
Avshalom Caspi ◽  
Terrie Moffitt

Abstract To further understand and measure the association between chronic inflammation, aging, and age-related diseases, broadly applicable standard biomarkers of systemic chronic inflammation are needed. We tested whether elevated blood levels of the emerging chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR) were associated with accelerated aging, lower functional capacity, and cognitive decline. We used data from the population-representative longitudinal Dunedin Study (N=875). Plasma suPAR levels were analyzed at ages 38 and 45 years. We performed regression analyses adjusted for sex, smoking, and C-reactive protein. suPAR levels increased from 2.39 ng/mL (SD 0.89) at age 38 to 3.01 (SD 1.03) at age 45 years. Elevated suPAR was associated with accelerated pace of biological aging across multiple organ systems (β 0.28, 95% CI 0.21–0.35), older facial appearance (β 0.16, 95% CI 0.10–0.22), and with structural signs of older brain age (β 0.06, 95% CI -0.00–0.13). Moreover, participants with higher suPAR levels had lower functional capacity (more physical limitations [β 0.24, 95% CI 0.18–0.30]; slower gait speed [β -0.14, 95% CI -0.20; -0.08]) and greater decline in cognitive function (β -0.07, 95% CI -0.13; -0.01) from childhood to adulthood compared to those with lower suPAR levels. Finally, improvements in health habits between age 38 and 45 (smoking cessation or increased physical activity) were associated with less steep increases in suPAR levels over those years. Our findings provide initial support for the utility of suPAR in studying the role of chronic inflammation in accelerated aging and functional decline.

Author(s):  
Line Jee Hartmann Rasmussen ◽  
Avshalom Caspi ◽  
Antony Ambler ◽  
Andrea Danese ◽  
Maxwell Elliott ◽  
...  

Abstract Background To understand and measure the association between chronic inflammation, aging, and age-related diseases, broadly applicable standard biomarkers of systemic chronic inflammation are needed. We tested whether elevated blood levels of the emerging chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR) were associated with accelerated aging, lower functional capacity, and cognitive decline. Methods We used data from the Dunedin Study, a population-representative 1972–1973 New Zealand birth cohort (n = 1037) that has observed participants to age 45 years. Plasma suPAR levels were analyzed at ages 38 and 45 years. We performed regression analyses adjusted for sex, smoking, C-reactive protein, and current health conditions. Results Of 997 still-living participants, 875 (88%) had plasma suPAR measured at age 45. Elevated suPAR was associated with accelerated pace of biological aging across multiple organ systems, older facial appearance, and with structural signs of older brain age. Moreover, participants with higher suPAR levels had greater decline in physical function and cognitive function from childhood to adulthood compared to those with lower suPAR levels. Finally, improvements in health habits between ages 38 and 45 (smoking cessation or increased physical activity) were associated with less steep increases in suPAR levels over those years. Conclusions Our findings provide initial support for the utility of suPAR in studying the role of chronic inflammation in accelerated aging and functional decline.


2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S870-S870
Author(s):  
Line Rasmussen ◽  
Avshalom Caspi ◽  
Terrie Moffitt ◽  
Harvey J Cohen ◽  
Miriam C Morey ◽  
...  

Abstract Background: Gait speed is a well-known predictor of functional decline and mortality in older adults, but little is known about the origins of gait speed earlier in life. We tested the hypothesis that slow gait reflects accelerated biological aging already at midlife, as well as poor neurocognitive functioning in childhood and childhood-to-midlife cognitive decline. Methods: Prospective study of the population-representative Dunedin Study birth cohort (n=1,037), followed to age 45 (until April 2019). We measured age-45 gait speed in 904 (90.7%) participants and tested associations with key life course factors. Results: The mean (SD) gait speeds (m/s) were: usual: 1.30 (0.17); dual task: 1.16 (0.23); and maximum: 1.99 (0.29). Among midlife adults, those with more physical limitations (β -0.27; P<.001), poorer physical functions (β 0.24–0.36; all P<.001), accelerated biological aging across multiple organ systems (β -0.33), older facial appearance (β -0.25), smaller brain volume (β 0.15), more cortical thinning (β 0.09), smaller cortical surface area (β 0.13), and more white matter hyperintensities (β -0.09) had slower gait speed, all P<.05. Participants with lower IQ in childhood (β 0.34) and midlife (β 0.38) and who exhibited childhood-to-midlife cognitive decline (β 0.10) had slower gait speed at midlife, all P<.01. Adults with poorer neurocognitive function as early as age 3 had slower gait in midlife (β 0.26; P<.001). Conclusion: Adults’ gait speed is more than an indicator of geriatric functional status, it is also an index of midlife aging and lifelong brain health.


2015 ◽  
Vol 112 (30) ◽  
pp. E4104-E4110 ◽  
Author(s):  
Daniel W. Belsky ◽  
Avshalom Caspi ◽  
Renate Houts ◽  
Harvey J. Cohen ◽  
David L. Corcoran ◽  
...  

Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their “biological aging” (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.


Author(s):  
Cathal McCrory ◽  
Giovanni Fiorito ◽  
Sinead McLoughlin ◽  
Silvia Polidoro ◽  
Cliona Ni Cheallaigh ◽  
...  

Abstract Allostatic load (AL) and epigenetic clocks both attempt to characterize the accelerated aging of biological systems, but at present it is unclear whether these measures are complementary or distinct. This study examines the cross-sectional association of AL with epigenetic age acceleration (EAA) in a subsample of 490 community-dwelling older adults participating in The Irish Longitudinal study on Aging (TILDA). A battery of 14 biomarkers representing the activity of four different physiological systems: immunological, cardiovascular, metabolic, renal, was used to construct the AL score. DNA methylation age was computed according to the algorithms described by Horvath, Hannum, and Levine allowing for estimation of whether an individual is experiencing accelerated or decelerated aging. Horvath, Hannum, and Levine EAA correlated 0.05, 0.03, and 0.21 with AL, respectively. Disaggregation by sex revealed that AL was more strongly associated with EAA in men compared with women as assessed using Horvath’s clock. Metabolic dysregulation was a strong driver of EAA in men as assessed using Horvath and Levine’s clock, while metabolic and cardiovascular dysregulation were associated with EAA in women using Levine’s clock. Results indicate that AL and the epigenetic clocks are measuring different age-related variance and implicate sex-specific drivers of biological aging.


2019 ◽  
Author(s):  
Anil P.S. Ori ◽  
Loes M. Olde Loohuis ◽  
Jerry Guintivano ◽  
Eilis Hannon ◽  
Emma Dempster ◽  
...  

AbstractSchizophrenia (SCZ) is a severe mental illness that is associated with an increased prevalence of age-related disability and morbidity compared to the general population. An accelerated aging process has therefore been hypothesized as a component of the SCZ disease trajectory. Here, we investigated differential aging using three DNA methylation (DNAm) clocks (i.e. Hannum, Horvath, Levine) in a multi-cohort SCZ whole blood sample consisting of 1,100 SCZ cases and 1,200 controls. It is known that all three DNAm clocks are highly predictive of chronological age and capture different features of biological aging. We found that blood-based DNAm aging is significantly altered in SCZ with age- and sexspecific effects that differ between clocks and map to distinct chronological age windows. Most notably, the predicted phenotypic age (Levine clock) in female cases, starting at age 36 and beyond, is 3.21 years older compared to matching control subjects (95% CI: 1.92-4.50, P=1.3e-06) explaining 7.7% of the variance in disease status. Female cases with high SCZ polygenic risk scores present the highest age acceleration in this age group with +7.03 years (95% CI: 3.87-10.18, P=1.7E-05). Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings suggests that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. These results provide new biological insights into the aging landscape of SCZ with age- and sexspecific effects and warrant further investigations into the potential of DNAm clocks as clinical biomarkers that may help with disease management in schizophrenia.


Author(s):  
Chia-Ling Kuo ◽  
Luke C. Pilling ◽  
Janice L Atkins ◽  
Jane AH Masoli ◽  
João Delgado ◽  
...  

AbstractWith no known treatments or vaccine, COVID-19 presents a major threat, particularly to older adults, who account for the majority of severe illness and deaths. The age-related susceptibility is partly explained by increased comorbidities including dementia and type II diabetes [1]. While it is unclear why these diseases predispose risk, we hypothesize that increased biological age, rather than chronological age, may be driving disease-related trends in COVID-19 severity with age. To test this hypothesis, we applied our previously validated biological age measure (PhenoAge) [2] composed of chronological age and nine clinical chemistry biomarkers to data of 347,751 participants from a large community cohort in the United Kingdom (UK Biobank), recruited between 2006 and 2010. Other data included disease diagnoses (to 2017), mortality data (to 2020), and the UK national COVID-19 test results (to May 31, 2020) [3]. Accelerated aging 10-14 years prior to the start of the COVID-19 pandemic was associated with test positivity (OR=1.15 per 5-year acceleration, 95% CI: 1.08 to 1.21, p=3.2×10−6) and all-cause mortality with test-confirmed COVID-19 (OR=1.25, per 5-year acceleration, 95% CI: 1.09 to 1.44, p=0.002) after adjustment for demographics including current chronological age and pre-existing diseases or conditions. The corresponding areas under the curves were 0.669 and 0.803, respectively. Biological aging, as captured by PhenoAge, is a better predictor of COVID-19 severity than chronological age, and may inform risk stratification initiatives, while also elucidating possible underlying mechanisms, particularly those related to inflammaging.


2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S893-S893
Author(s):  
Albert T Higgins-Chen ◽  
Christiaan Vinkers ◽  
Marco P Boks ◽  
Morgan E Levine

Abstract Schizophrenia (SZ) is associated with large increases in all-cause mortality, high smoking rates, and elevated levels of age-associated proteins—suggesting individuals with SZ may experience accelerated rates of biological aging. Yet surprisingly, multiple previous studies found no association between SZ and biological age using Horvath’s epigenetic clock, a well-recognized and validated biomarker of aging based on DNA methylation (DNAm) levels. However, numerous epigenetic clocks have been developed to date, many of which are better indicators of differential lifespan and healthspan than the original Horvath clock. Thus, we hypothesize that these epigenetic clocks may be better proxies for the presumed accelerated aging rate in SZ. Here we investigate 14 epigenetic clocks using three publicly available DNAm datasets from whole blood, comparing SZ to non-psychiatric controls (NPC). In all data sets, we find SZ age acceleration in three clocks previously shown to be most predictive of age-related morbidity and mortality risk. In contrast, two clocks developed to capture mitotic rate are decelerated in SZ, consistent with low cancer rates despite smoking observed in epidemiological studies of SZ. We use these clocks to investigate the determinants of altered aging in SZ, such as smoking, alcohol, BMI, age-associated proteins, blood cell composition, and psychotropic medications. Principal component analysis suggests mortality clock acceleration, mitotic clock deceleration, and medication effects are independent phenomena in SZ. Our study demonstrates the importance of studying the various epigenetic clocks in tandem and highlights their potential utility for understanding how mental illness influences long-term outcomes including cancer and early mortality.


2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S833-S833
Author(s):  
Christy S Carter ◽  
Michal Masternak ◽  
Thomas W Buford

Abstract The human intestinal tract (i.e., “gut”) is inhabited by over 100 trillion microorganisms; including over 1000 species of known bacteria. These organisms have co-evolved with humans over millennia to live together for mutual benefit. Though long overlooked in considerations of human health and disease treatment, gut microorganisms are highly involved in numerous metabolic reactions which influence normal host physiology. A variety of biologic, medical, and lifestyle factors appear to contribute to gut dysbiosis in late-life, and interventions specifically designed to target these factors may be useful in restoring microbial balance. Evidence from both clinical and preclinical studies suggests that gut dysbiosis is related to age-related inflammation as well as age-related conditions including frailty, Alzheimer’s disease, and perhaps even longevity. Crosstalk between the gut and multiple organ systems (brain, heart, muscle etc.) may lead to the development of age-related diseases and loss of physiological function, although the signals are not well understood. In this symposium we address the broad topic of the Gut Microbiome and Aging by presenting evidence from multiple model systems (mice, rats and monkeys) and provide a forum to discuss critical areas of research for moving forward.


2005 ◽  
Vol 33 (6) ◽  
pp. 650-674 ◽  
Author(s):  
Kevin P. Keenan ◽  
Chao-Min Hoe ◽  
Lori Mixson ◽  
Carol L. Mccoy ◽  
John B. Coleman ◽  
...  

This study compared the effects of ad libitum (AL) overfeeding and moderate or marked dietary restriction (DR) on the pathogenesis of a metabolic syndrome of diabesity comprised of age-related degenerative diseases and obesity in a outbred stock of Sprague–Dawley (SD) rats [Crl:CD (SD) IGS BR]. SD rats were fed Purina Certified Rodent Diet AL (group 1), DR at 72–79% of AL (group 2), DR at 68–72% of AL (group 3) or DR at 47–48% of AL (group 4) for 106 weeks. Interim necropsies were performed at 13, 26, and 53 weeks, after a 7-day 5-bromo-2-deoxyuridine (BrdU)-filled minipump implantation. Body weights, organ weights, carcass analysis, in-life data including estrous cyclicity, and histopathology were determined. At 6–7 weeks of age SD rats had 6% body fat. AL-feeding resulted in hypertriglyceridemia, hypercholesterolemia, and dietary-induced obesity (DIO) by study week 14, with 25% body fat that progressed to 36–42% body fat by 106 weeks. As early as 14 weeks, key biomarkers developed for spontaneous nephropathy, cardiomyopathy, and degenerative changes in multiple organ systems. Early endocrine disruption was indicated by changes in metabolic and endocrine profiles and the early development and progression of lesions in the pituitary, pancreatic islets, adrenals, thyroids, parathyroids, liver, kidneys, and other tissues. Reproductive senescence was seen by 9 months with declines in estrous cyclicity and pathological changes in the reproductive organs of both sexes fed AL or moderate DR, but not marked DR. The diabesity syndrome in AL-fed, DIO SD rats was readily modulated or prevented by moderate to marked DR. Moderate DR of balanced diets resulted in a better toxicology model by significantly improving survival, controlling adult body weight and obesity, reducing the onset, severity, and morbidity of age-related renal, endocrine, metabolic, and cardiac diseases. Moderate DR feeding reduces study-to-study variability, increases treatment exposure time, and increases the ability to distinguish true treatment effects from spontaneous aging. The structural and metabolic differences between the phenotypes of DIO and DR SD rats indicated changes of polygenic expression over time in this outbred stock. AL-overfeeding of SD rats produces a needed model of DIO and diabesity that needs further study of its patterns of polygenic expression and phenotype.


2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S348-S348
Author(s):  
Daniel W Belsky

Abstract Our aging global population presents a new set of challenges for public health. Individual-disease focused models are becoming outmoded as geriatricians recognize multimorbidity and frailty as the central challenges in preserving health for older adults. Evidence from research into the biology of aging suggests that a set of common cellular-level processes underpin decline in system integrity that induces vulnerability to disease across multiple organ systems, including the brain. In parallel, research in life-course gerontology indicates that the roots of aging-related decline in system integrity extend from early life and encompass histories of social, psychological, and biochemical exposures. The research presented in this symposium aims to integrate these emerging paradigms in aging research by mapping connections among measures of aging in the brain and body and social, psychological, and nutrition exposures. Our symposium focuses on (1) links between social-psychological determinants of health and biological aging in the brain and body; and (2) social and behavioral protective factors that may buffer emerging biological risk in aging. The overarching goal of this symposium is to introduce an approach to gerontology that integrates geroscience with life-course social and psychiatric epidemiology to advance understanding of cognitive aging and functional decline, and ultimately identify novel interventions to extend healthy lifespan.


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