马赛克染色体突变（mCAs）是与衰老、癌症、心血管疾病、传染病和死亡相关的结构性突变。 mCAs在百岁老人和具有家族长寿的人中的分布尚不清楚。我们使用MOsaic CHromosomal Alteration（MoChA）在新英格兰百岁老人研究（NECS）的2050名百岁老人、子女和248个对照组以及长寿家庭研究（LLFS）的3642名具有家族长寿和920名配偶对照中发现mCAs。我们分析了体细胞mCAs与年龄、家族长寿、年龄相关疾病的发病率和死亡率之间的研究特定关联，并通过元分析综合结果。我们发现，100KB以上的mCA积累在102岁时会增加，并在更高的年龄呈平台状态。相对于对照组，百岁老人和子女积累的常染色体mCAs较少（相对风险0.637，p = 0.0147）。具有APOE E4等位基因的受试者积累常染色体mCAs的风险高35.3％（p = 0.002）。男性发生mCAs风险比女性高（男性相对风险1.36，p = 5.15e-05）。在10％虚假发现率下，mCAs与癌症（危险比1.2）和痴呆（危险比1.259）的发病率增加有关。我们观察到mCAs与死亡风险之间存在边际显著相关（危险比1.07，p = 0.0605）。我们的结果表明，具有mCAs的个体的普遍性在102岁以上的年龄不会继续增加，促进家族长寿的因素似乎能够保护不受mCAs的侵害。这些结果表明，有限的mCA积累可能是极端人类长寿的一个重要机制，值得研究。©2023年作者。由牛津大学出版社代表美国老年学会出版。保留所有权利。有关许可，请发送电子邮件至：journals.permissions@oup.com。

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 3642 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 > 100KB increased to 102 years and plateaued at older ages. Centenarians and offspring accumulated fewer autosomal mCAs compared to controls (relative risk 0.637, p=0.0147). Subjects with the APOE E4 allele had a 35.3% higher risk of accumulating autosomal mCAs (p=0.002). 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=0.0605). 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.© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.