Mosaic Chromosomal Alterations and Human Longevity

Abstract

Mosaic chromosomal alterations (mCAs) are structural alterations associated with aging, cancer, cardiovascular disease, infectious diseases, and mortality. The distribution of mCAs in centenarians and individuals with familial longevity is poorly understood. We used MOsaic CHromosomal Alteration (MoChA) to discover mCAs in 2050 centenarians, offspring, and 248 controls from the New England Centenarian Study (NECS) and in 3 642 subjects with familial longevity and 920 spousal controls from the Long-Life Family Study (LLFS). We analyzed study-specific associations of somatic mCAs with age, familial longevity, the incidence of age-related diseases, and mortality and aggregated the results by meta-analysis. We show that the accumulation of mCAs > 100 KB increased to 102 years and plateaued at older ages. Centenarians and offspring accumulated fewer autosomal mCAs compared with controls (relative risk 0.637, p = .0147). Subjects with the APOE E4 allele had a 35.3% higher risk of accumulating autosomal mCAs (p = .002). Males were at higher risk for mCAs compared to females (male relative risk 1.36, p = 5.15e-05). mCAs were associated with increased hazard for cancer (hazard ratio 1.2) and dementia (hazard ratio 1.259) at a 10% false discovery rate. We observed a borderline significant association between mCAs and risk for mortality (hazard ratio 1.07, p = .0605). Our results show that the prevalence of individuals with mCAs does not continue to increase at ages >102 years and factors promoting familial longevity appear to confer protections from mCAs. These results suggest that limited mCA accumulation could be an important mechanism for extreme human longevity that needs to be investigated.

Keywords: Aging; Clonal hematopoiesis; Mosaicism.

Figure 1.

The detected autosomal mCA in the NECS and the LLFS data sets. (A) The prevalence of subjects with the detected autosomal mCA over age ranges for longevity-related cohort (red) and controls (blue) in NECS (upper panel) and frequency of the enrolled subjects over age ranges (lower panel). The graph demonstrates an increase in the proportion of subjects with mCA in the longevity-related cohort with age up till 102 years and then plateaus at older ages suggesting that mCAs are incompatible with extreme human longevity. (B) Prevalence of subjects with autosomal mCA over age ranges for longevity-related cohort (red) and controls (blue) in LLFS (upper panel) and frequency of the enrolled subjects over different age ranges (lower panel). The plot demonstrates a steady increase in the proportion of subjects with autosomal mCA in longevity-related cohort in LLFS with age. The lack of subjects aged 105 and older in LLFS does not allow to confirm the trend discovered in NECS. (C) The detected mCAs in NECS and LLFS. The detected mCAs (shown as dots) plotted by the location on the genome over the estimated cell fraction in the samples. The size of a dot reflects the size of mCA in Mega base pairs, and the color/shades of grey illustrates the predicted mCA type: on the left—in the LLFS data, on the right—in the NECS data. CN-OH = Copy Neutral loss of heterozygosity; LLFS = Long-Life Family Study; mCA = mosaic chromosomal alteration; NECS = New England Centenarian Study.