Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, 199 Aba Khoushy Ave., 3498838, Mount Carmel, Haifa, Israel.
Geroscience. 2024 Oct;46(5):4147-4162. doi: 10.1007/s11357-024-01178-0. Epub 2024 May 9.
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.
衰老是一个过程，或衰老，其特征是身体和生理功能的特定年龄下降，脆弱性增加和基因组变化，包括突变积累。然而，基因组结构变化影响人类寿命的机制仍然不清楚。拷贝数变异（CNVs）是基因组变异的丰富类别，为理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 名阿什肯纳兹犹太百岁老人、他们的后代和无关对照组中的 CNV 谱。这些组的平均年龄分别为 97.4±2.8、69.2±9.2 和 66.5±7.0。这是我们第一次比较不同大小类别的 CNVs，从 1kb 到 100MB。我们使用一种高分辨率的定制 Affymetrix 阵列，靶向 44639 个基因组区域，在百岁老人、他们的后代和对照组中分别鉴定出总共 12166、22188 和 10285 个 CNVs。有趣的是，后代组显示出最多的独特 CNVs，其次是对照组和百岁老人组。虽然在所有三组中都发现了增益和缺失，但百岁老人组相对于对照组，总增益和总缺失的平均数量明显更高（p<0.0327，0.0182）。此外，百岁老人组丢失的基因组物质总长度较低，表明他们随着时间的推移可能保持更好的基因组完整性。我们还观察到后代中 CNVs 的倍数增加，这意味着它们具有更高的基因组完整性和长寿保存的潜在机制。经历丢失或增益的基因组区域似乎分布在基因组的许多位点上，包含参与 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，百岁老人中观察到的异常长寿可能归因于对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的内在组成部分。此外，本研究中观察到的较长 CNVs 与差异基因表达之间的强烈关联支持了基因组完整性可能对长寿产生积极影响的观点。
