Accelerated bio‐cognitive aging in Down syndrome: State of the art and possible deceleration strategies

Abstract

Down syndrome (DS) has been proposed by George Martin as a segmental progeroid syndrome since 1978. In fact, DS persons suffer from several age‐associated disorders much earlier than euploid persons. Furthermore, a series of recent studies have found that DS persons display elevated levels of age biomarkers, thus supporting the notion that DS is a progeroid trait. Nowadays, due to the progressive advancements in social inclusion processes and medical assistance, DS persons live much longer than in the past; therefore, the early‐onset health problems of these persons are becoming an urgent and largely unmet social and medical burden. In particular, the most important ailment of DS persons is the accelerated cognitive decline that starts when they reach about 40 years of age. This decline can be at least in part counteracted by multi‐systemic approaches including early‐onset cognitive training, physical activity, and psychosocial assistance. However, no pharmacological treatment is approved to counteract this decline. According to the most advanced conceptualization of Geroscience, tackling the molecular mechanisms underpinning the aging process should be a smart/feasible strategy to combat and/or delay the great majority of age‐related diseases, including cognitive decline. We think that a debate is needed urgently on if (and how) this strategy could be integrated in protocols to face DS‐associated dementia and overall unhealthy aging. In particular we propose that, on the basis of data obtained in different clinical settings, metformin is a promising candidate that could be exploited to counteract cognitive decline in DS.

Age-related DNA methylation changes are sex-specific: a comprehensive assessment

“…In the present study we aimed at filling this gap by exploiting 4 large EWAS studies on human whole blood, including men and women of different ages and populations, in which we analyzed the sex specificity of age-associated normative changes, variability, epimutations and entropy. The main findings we will discuss are the following: i) a large fraction of probes with sex-specific DNA methylation undergoes also hyper-or hypo-methylation during aging, and a small number of probes showed significant age-by-sex interaction; ii) the methylation of 2 selected saDMPs, aping in FIGN and PRR4 genes, is differently modulated in centenarians and Down syndrome persons, assumed as human models of successful and unsuccessful aging [14,34,35]; iii) males display a higher number of saVMPs respect to females, the vast majority of which show age-associated increase in methylation variability; iv) males and females do not differ for the age-associated increase in epimutations and in entropy.…”

“…Although less evident, also CpG 5 showed sex-related differences in age-associated methylation changes (Supplementary Figure 4). We used the EpiTYPER assay to investigate the two validated loci in samples from additional cohorts available in our laboratory: persons affected by Down syndrome, that we previously demonstrated to have an acceleration in epigenetic age [34,35]; and centenarians and their offspring, as a model of successful aging experiencing a deceleration in epigenetic age [14]. Interestingly, we found sex-dependent patterns of FIGN and PRR4 methylation also in these models.…”

“…Another question is if and how the saDMPs that we identified contribute to the sex gap in health span and longevity. To this aim, we exploited two cohorts available in our lab, in which we measured whole blood DNA methylation by the targeted EpiTYPER assay: persons affected by Down syndrome, as a model of premature/accelerated aging [34,35], and centenarians, as a model of successful/decelerated aging [14]. The results are intriguing, as both models showed a peculiar sex specific alteration in FIGN and PRR4 epigenetic patterns.…”

Maternal Choline Supplementation Alters Basal Forebrain Cholinergic Neuron Gene Expression in the Ts65Dn Mouse Model of Down Syndrome

“…While there is significant intra-individual variability in the degree of physiological and cognitive dysfunction, intellectual disability (ID) is considered a hallmark of DS (Epstein, 1995;Maatta et al, 2006). Compounding the ID seen in individuals with DS is a premature aging phenotype (Franceschi et al, 2019) that includes a neuropathological profile similar to that seen in Alzheimer's disease (AD), namely, the deposition of amyloid-beta (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs) by early midlife, accompanied by a clinical presentation of dementia in >50% of individuals over the age of 50 (Thase, 1982;Mann et al, 1984;Wisniewski et al, 1985a;1985b;Hof et al, 1995;Wegiel et al, 1996;Dekker et al, 2018;Perez et al, 2019).…”

Age-related trajectories of DNA methylation network markers: a parenclitic network approach to a family-based cohort of patients with Down Syndrome

“…DS is considered a segmental progeroid syndrome, as a phenotype of premature/accelerated aging occurs in a subset of organs and systems, including the immune and the nervous systems 24,25 . Among the progeroid phenotypes of DS, the high rate and early occurrence (by the age of 40 years) of Alzheimer's disease is one of the most prominent 26 .…”