Karasik David, Newman Anne
Hebrew Senior Life Institute for Aging Research, 1200 Centre Street, 02131, Boston, MA, USA,
Adv Exp Med Biol. 2015;847:141-61. doi: 10.1007/978-1-4939-2404-2_7.
Genetic studies have bestowed insight into the biological mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms’ aging. Recent advances in molecular and genetic epidemiology provide tools to explore the genetic sources of the variability in biological aging in humans. To be successful, the genetic study of a complex condition such as aging requires the clear definition of essential traits that can characterize the aging process phenotypically. Phenotypes of human aging have long relied on mortality rate or exceptional longevity. Genome-wide association studies (GWAS) have been shown to present an unbiased approach to the identification of new candidate genes for human diseases. The GWAS approach can also be used for positive health phenotypes such as longevity or a delay in age-related chronic disease, as well as for other age related changes such as loss of telomere length or lens transparency. Sequencing, either in targeted regions or across the whole genome can further identify rare variation that may contribute to the biological aging mechanisms. To date, the results of the GWAS for longevity are rather disappointing, possibly in part due to the small number of individuals with GWAS data who have reached advanced old age.Human aging phenotypes are needed that can be assessed prior to death, and should be both heritable and validated as predictors of longevity. Potentially, phenotypes that focus on “successful” or “healthy” aging will be more powerful as they can be measured in large numbers of people and also are clinically relevant.We postulate that construction of an integrated phenotype of aging can be achieved capitalizing on multiple traits that may have weak correlations, but a shared underlying genetic architecture. This is based on a hypothesis that convergent results from multiple individual aging-related traits will point out the pleiotropic signals responsible for the overall rate of aging of the organism. An approach would be to investigate traits that are linked to the state of many vital functions, disability, and ultimately survival rates, to identify common biological pathways that govern aging processes in humans. New composite aging phenotypes must be validated by predicting all-cause mortality, major chronic disease and disability late in life.
基因研究使人们深入了解了个体对生物体衰老易感性（或抗性）差异背后的生物学机制。分子和基因流行病学的最新进展提供了探索人类生物衰老变异性遗传来源的工具。要取得成功，对诸如衰老这样的复杂状况进行基因研究需要明确界定能够从表型上表征衰老过程的基本特征。人类衰老的表型长期以来一直依赖于死亡率或超长寿命。全基因组关联研究（GWAS）已被证明是一种用于识别人类疾病新候选基因的无偏方法。GWAS方法也可用于诸如长寿或与年龄相关的慢性病延迟等积极健康表型，以及用于其他与年龄相关的变化，如端粒长度丧失或晶状体透明度降低。在靶向区域或全基因组进行测序可以进一步识别可能有助于生物衰老机制的罕见变异。迄今为止，GWAS针对长寿的研究结果相当令人失望，这可能部分是由于拥有GWAS数据且已步入高龄的个体数量较少。需要能够在死亡前进行评估的人类衰老表型，并且这些表型应该是可遗传的，并经过验证可作为长寿的预测指标。潜在地，关注“成功”或“健康”衰老的表型可能会更有说服力，因为它们可以在大量人群中进行测量，并且在临床上也具有相关性。我们假设，可以利用多个可能具有弱相关性但具有共同潜在遗传结构的特征来构建衰老的综合表型。这是基于这样一种假设，即来自多个与个体衰老相关特征的趋同结果将指出负责生物体整体衰老速率的多效性信号。一种方法是研究与许多重要功能状态、残疾以及最终生存率相关的特征，以识别控制人类衰老过程的共同生物学途径。新的复合衰老表型必须通过预测全因死亡率、主要慢性病和晚年残疾来进行验证。
