Accelerated biological aging in people with Down syndrome with full and segmental trisomy 21 begins in childhood as revealed by immunoglobulin G glycosylation

Abstract Cells from people with Down syndrome (DS) show faster accumulation of DNA damage and epigenetic aging marks. Causative mechanisms remain un-proven and hypotheses range from amplified chromosomal instability to actions of several supernumerary chromosome 21 genes. Plasma immunoglobulin G (IgG) glycosylation profiles are established as a reliable predictor of biological and chronological aging. We performed IgG glycan profiling of n=246 individuals with DS (208 adults and 38 children) from three European populations and compared these to age-, sex- and demography-matched general populations. We uncovered very significantly increased IgG glycosylation aging marks associated with DS. Average levels of IgG glycans without galactose (G0) and those with two galactoses (G2) as a function of age in persons with DS corresponded to levels detected in 19 years older euploid individuals. Some aging marks were significant already in children with DS. Remarkably, the IgG glycan profiles of a child with segmental duplication of only 31 genes on chromosome 21 had values similar to those of age-matched DS children, outside the normal children’s range. This is the first non-epigenetic evidence of accelerated systemic biological aging in DS, suggesting it begins very early in childhood. It points to a causative contribution of the overdose of genes in a short segment of chromosome 21, not previously linked to accelerated aging, opening a route to discovery of hitherto unrecognised mechanisms.

Download Full-text

Schizophrenia is characterized by age- and sex-specific effects on epigenetic aging

10.1101/727859 ◽

2019 ◽

Cited By ~ 2

Author(s):

Anil P.S. Ori ◽

Loes M. Olde Loohuis ◽

Jerry Guintivano ◽

Eilis Hannon ◽

Emma Dempster ◽

...

Keyword(s):

Accelerated Aging ◽

Disease Status ◽

Risk Scores ◽

Chronological Age ◽

Biological Aging ◽

Disease Trajectory ◽

Clinical Biomarkers ◽

Age Related ◽

Epigenetic Aging ◽

Increased Risk

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.

Download Full-text

Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.700280 ◽

2021 ◽

Vol 13 ◽

Author(s):

Xu-Qiao Chen ◽

Zhuo Xing ◽

Quang-Di Chen ◽

Richard J. Salvi ◽

Xuming Zhang ◽

...

Keyword(s):

Hearing Loss ◽

Down Syndrome ◽

Immune System ◽

Clinical Manifestations ◽

Chromosome 21 ◽

Growth Delay ◽

Biological Aging ◽

Dependent Manner ◽

Age Related ◽

The Impact

Down syndrome (DS) is the most common genetic cause of Alzheimer’s disease (AD) due to trisomy for all or part of human chromosome 21 (Hsa21). It is also associated with other phenotypes including distinctive facial features, cardiac defects, growth delay, intellectual disability, immune system abnormalities, and hearing loss. All adults with DS demonstrate AD-like brain pathology, including amyloid plaques and neurofibrillary tangles, by age 40 and dementia typically by age 60. There is compelling evidence that increased APP gene dose is necessary for AD in DS, and the mechanism for this effect has begun to emerge, implicating the C-terminal APP fragment of 99 amino acid (β-CTF). The products of other triplicated genes on Hsa21 might act to modify the impact of APP triplication by altering the overall rate of biological aging. Another important age-related DS phenotype is hearing loss, and while its mechanism is unknown, we describe its characteristics here. Moreover, immune system abnormalities in DS, involving interferon pathway genes and aging, predispose to diverse infections and might modify the severity of COVID-19. All these considerations suggest human trisomy 21 impacts several diseases in an age-dependent manner. Thus, understanding the possible aging-related mechanisms associated with these clinical manifestations of DS will facilitate therapeutic interventions in mid-to-late adulthood, while at the same time shedding light on basic mechanisms of aging.

Download Full-text

Losing Years Doing Time: Incarceration Exposure and Accelerated Biological Aging among African American Adults

Journal of Health and Social Behavior ◽

10.1177/00221465211052568 ◽

2021 ◽

pp. 002214652110525

Author(s):

Mark T. Berg ◽

Ethan M. Rogers ◽

Man-Kit Lei ◽

Ronald L. Simons

Keyword(s):

African American ◽

Accelerated Aging ◽

Premature Mortality ◽

Health Study ◽

Biological Aging ◽

Formerly Incarcerated ◽

African American Adults ◽

Epigenetic Aging ◽

The Family ◽

Using Data

Research suggests that incarceration exposure increases the prevalence of morbidity and premature mortality. This work is only beginning to examine whether the stressors of the incarceration experience become biologically embedded in ways that affect physiological deterioration. Using data from a longitudinal sample of 410 African American adults in the Family and Community Health Study and an epigenetic index of aging, this study tests the extent to which incarceration accelerates epigenetic aging and whether experiences with violence moderate this association. Results from models that adjust for selection effects suggest that incarceration exposure predicted accelerated aging, leaving formerly incarcerated African American individuals biologically older than their calendar age. Direct experiences with violence also exacerbated the effects of incarceration. These findings suggest that incarceration possibly triggers a stress response that affects a biological signature of physiological deterioration.

Download Full-text

Aging with Down Syndrome—Where Are We Now and Where Are We Going?

Journal of Clinical Medicine ◽

10.3390/jcm10204687 ◽

2021 ◽

Vol 10 (20) ◽

pp. 4687

Author(s):

Melissa J. Alldred ◽

Alessandra C. Martini ◽

David Patterson ◽

James Hendrix ◽

Ann-Charlotte Granholm

Keyword(s):

Down Syndrome ◽

Neuronal Loss ◽

Accelerated Aging ◽

Research Field ◽

Chromosome 21 ◽

Research Areas ◽

Genes Encoding ◽

The Usa ◽

History Of ◽

The Brain

Down syndrome (DS) is a form of accelerated aging, and people with DS are highly prone to aging-related conditions that include vascular and neurological disorders. Due to the overexpression of several genes on Chromosome 21, for example genes encoding amyloid precursor protein (APP), superoxide dismutase (SOD), and some of the interferon receptors, those with DS exhibit significant accumulation of amyloid, phospho-tau, oxidative stress, neuronal loss, and neuroinflammation in the brain as they age. In this review, we will summarize the major strides in this research field that have been made in the last few decades, as well as discuss where we are now, and which research areas are considered essential for the field in the future. We examine the scientific history of DS bridging these milestones in research to current efforts in the field. We extrapolate on comorbidities associated with this phenotype and highlight clinical networks in the USA and Europe pursuing clinical research, concluding with funding efforts and recent recommendations to the NIH regarding DS research.

Download Full-text

Towards a large-scale assessment of the relationship between biological and chronological aging: The INSPIRE Mouse Cohort

Journal of Frailty & Aging ◽

10.14283/jfa.2020.43 ◽

2020 ◽

pp. 1-11

Author(s):

Y. Santin ◽

S. Lopez ◽

I. Ader ◽

S. Andrieu ◽

N. Blanchard ◽

...

Keyword(s):

Large Scale ◽

Healthy Aging ◽

Biological Fluids ◽

Clinical Signs ◽

Accelerated Aging ◽

Chronological Age ◽

Biological Aging ◽

Chronological Aging ◽

Exercise Interventions ◽

Early Signs

Aging is the major risk factor for the development of chronic diseases. After decades of research focused on extending lifespan, current efforts seek primarily to promote healthy aging. Recent advances suggest that biological processes linked to aging are more reliable than chronological age to account for an individual’s functional status, i.e. frail or robust. It is becoming increasingly apparent that biological aging may be detectable as a progressive loss of resilience much earlier than the appearance of clinical signs of frailty. In this context, the INSPIRE program was built to identify the mechanisms of accelerated aging and the early biological signs predicting frailty and pathological aging. To address this issue, we designed a cohort of outbred Swiss mice (1576 male and female mice) in which we will continuously monitor spontaneous and voluntary physical activity from 6 to 24 months of age under either normal or high fat/high sucrose diet. At different age points (6, 12, 18, 24 months), multiorgan functional phenotyping will be carried out to identify early signs of organ dysfunction and generate a large biological fluids/feces/organs biobank (100,000 samples). A comprehensive correlation between functional and biological phenotypes will be assessed to determine: 1) the early signs of biological aging and their relationship with chronological age; 2) the role of dietary and exercise interventions on accelerating or decelerating the rate of biological aging; and 3) novel targets for the promotion of healthy aging. All the functional and omics data, as well as the biobank generated in the framework of the INSPIRE cohort will be available to the aging scientific community. The present article describes the scientific background and the strategies employed for the design of the INSPIRE Mouse cohort.

Download Full-text