The aging process, or senescence, is characterized by age-specific decline in physical and physiological function, and increased frailty and genomic changes, including mutation accumulation. However, the mechanisms through which changes in genomic architecture influence human longevity have remained obscure. Copy number variants (CNVs), an abundant class of genomic variants, offer unique opportunities for understanding age-related genomic changes. Here we report the spectrum of CNVs in a cohort of 670 Ashkenazi Jewish centenarians, their progeny, and unrelated controls. The average ages of these groups were 97.4 ± 2.8, 69.2 ± 9.2, and 66.5 ± 7.0 respectively. For the first time, we compared different size classes of CNVs, from 1 kB to 100 MB in size. Using a high-resolution custom Affymetrix array, targeting 44,639 genomic regions, we identified a total of 12,166, 22,188, and 10,285 CNVs in centenarians, their progeny, and control groups, respectively. Interestingly, the offspring group showed the highest number of unique CNVs, followed by control and centenarians. While both gains and losses were found in all three groups, centenarians showed a significantly higher average number of both total gains and losses relative to their controls (p < 0.0327, 0.0182, respectively). Moreover, centenarians showed a lower total length of genomic material lost, suggesting that they may maintain superior genomic integrity over time. We also observe a significance fold increase of CNVs among the offspring, implying greater genomic integrity and a putative mechanism for longevity preservation. Genomic regions that experienced loss or gains appear to be distributed across many sites in the genome and contain genes involved in DNA transcription, cellular transport, developmental pathways, and metabolic functions. Our findings suggest that the exceptional longevity observed in centenarians may be attributed to the prolonged maintenance of functionally important genes. These genes are intrinsic to specific genomic regions as well as to the overall integrity of the genomic architecture. Additionally, a strong association between longer CNVs and differential gene expression observed in this study supports the notion that genomic integrity could positively influence longevity.

衰老过程或衰老的特点是身体和生理功能的年龄特异性下降，以及衰弱和基因组变化的增加，包括突变积累。然而，基因组结构的变化影响人类寿命的机制仍不清楚。拷贝数变异 (CNV) 是一类丰富的基因组变异，为了解与年龄相关的基因组变化提供了独特的机会。在这里，我们报告了 670 名德系犹太百岁老人、他们的后代以及不相关对照的 CNV 谱。这些组的平均年龄分别为97.4±2.8岁、69.2±9.2岁和66.5±7.0岁。我们首次比较了不同大小类别的 CNV，大小从 1 kB 到 100 MB。使用高分辨率定制 Affymetrix 阵列，针对 44,639 个基因组区域，我们在百岁老人、其后代和对照组中分别鉴定出总共 12,166、22,188 和 10,285 个 CNV。有趣的是，后代组显示出最多数量的独特 CNV，其次是对照组和百岁老人。虽然在所有三组中都发现了增益和损失，但百岁老人相对于对照组的总增益和损失的平均数显着更高（分别为p  < 0.0327 和 0.0182）。此外，百岁老人丢失的基因组材料总长度较低，这表明他们可能随着时间的推移保持较高的基因组完整性。我们还观察到后代中 CNV 显着增加，这意味着基因组完整性更高，并且是长寿保存的假定机制。经历损失或增加的基因组区域似乎分布在基因组中的许多位点，并且包含涉及 DNA 转录、细胞运输、发育途径和代谢功能的基因。我们的研究结果表明，在百岁老人中观察到的超长寿命可能归因于功能重要基因的长期维持。这些基因是特定基因组区域以及基因组结构整体完整性所固有的。此外，本研究中观察到的较长 CNV 与差异基因表达之间的密切关联支持了基因组完整性可以对寿命产生积极影响的观点。