The trajectory of frailty in older adults is important to public health; therefore, markers that may help predict this and other important outcomes could be beneficial. Epigenetic clocks have been developed and are associated with various health-related outcomes and sociodemographic factors, but associations with frailty are poorly described. Further, it is uncertain whether newer generations of epigenetic clocks, trained on variables other than chronological age, would be more strongly associated with frailty than earlier developed clocks. Using data from the Canadian Longitudinal Study on Aging (CLSA), we tested the hypothesis that clocks trained on phenotypic markers of health or mortality (i.e., Dunedin PoAm, GrimAge, PhenoAge and Zhang in Nat Commun 8:14617, 2017) would best predict changes in a 76-item frailty index (FI) over a 3-year interval, as compared to clocks trained on chronological age (i.e., Hannum in Mol Cell 49:359–367, 2013, Horvath in Genome Biol 14:R115, 2013, Lin in Aging 8:394–401, 2016, and Yang Genome Biol 17:205, 2016). We show that in 1446 participants, phenotype/mortality-trained clocks outperformed age-trained clocks with regard to the association with baseline frailty (mean = 0.141, SD = 0.075), the greatest of which is GrimAge, where a 1-SD increase in ΔGrimAge (i.e., the difference from chronological age) was associated with a 0.020 increase in frailty (95% CI 0.016, 0.024), or ~ 27% relative to the SD in frailty. Only GrimAge and Hannum (Mol Cell 49:359–367, 2013) were significantly associated with change in frailty over time, where a 1-SD increase in ΔGrimAge and ΔHannum 2013 was associated with a 0.0030 (95% CI 0.0007, 0.0050) and 0.0028 (95% CI 0.0007, 0.0050) increase over 3 years, respectively, or ~ 7% relative to the SD in frailty change. Both prevalence and change in frailty are associated with increased epigenetic age. However, not all clocks are equally sensitive to these outcomes and depend on their underlying relationship with chronological age, healthspan and lifespan. Certain clocks were significantly associated with relatively short-term changes in frailty, thereby supporting their utility in initiatives and interventions to promote healthy aging.

中文翻译：

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在加拿大老龄化纵向研究中，表观遗传年龄与虚弱的基线和 3 年变化有关

老年人虚弱的轨迹对公共卫生很重要；因此，可能有助于预测这一结果和其他重要结果的标记可能是有益的。表观遗传时钟已经开发出来，并与各种健康相关结果和社会人口学因素相关，但与虚弱的关联描述得很少。此外，还不确定新一​​代的表观遗传时钟是否比早期开发的时钟更容易与虚弱相关。使用来自加拿大老龄化纵向研究 (CLSA) 的数据，我们检验了时钟在健康或死亡率表型标记上训练的假设（即在 Nat Commun 8:14617 中的但尼丁 PoAm、GrimAge、PhenoAge 和 Zhang，2017) 最好预测 76 项虚弱指数 (FI) 在 3 年的时间间隔内的变化，与按实足年龄训练的时钟相比（即，Hannum in Mol Cell 49:359–367, 2013, Horvath in Genome Biol 14:R115, 2013, Lin in Aging 8:394–401, 2016, and Yang Genome Biol 17:205, 2016)。我们表明，在 1446 名参与者中，表型/死亡率训练时钟在与基线虚弱的关联方面优于年龄训练时钟（平均值 = 0.141，SD = 0.075），其中最大的是 GrimAge，其中 1-SD 增加ΔGrimAge（即与实际年龄的差异）与虚弱增加 0.020 相关（95% CI 0.016, 0.024），或相对于虚弱 SD 增加约 27%。只有 GrimAge 和 Hannum (Mol Cell 49:359–367, 2013) 与虚弱随时间的变化显着相关，其中 ΔGrimAge 和 ΔHannum 2013 增加 1-SD 分别与 0.0030 (95% CI 0.0007, 0.0050) 和 0.0028 (95% CI 0.0007, 0.0050) 在 3 年内增加，或相对于 SD 增加约 7%脆弱的变化。衰弱的患病率和变化都与表观遗传年龄的增加有关。然而，并非所有时钟都对这些结果同样敏感，并且取决于它们与实足年龄、健康寿命和寿命的潜在关系。某些时钟与相对短期的虚弱变化显着相关，从而支持它们在促进健康老龄化的倡议和干预中的效用。衰弱的患病率和变化都与表观遗传年龄的增加有关。然而，并非所有时钟都对这些结果同样敏感，并且取决于它们与实足年龄、健康寿命和寿命的潜在关系。某些时钟与相对短期的虚弱变化显着相关，从而支持它们在促进健康老龄化的倡议和干预中的效用。衰弱的患病率和变化都与表观遗传年龄的增加有关。然而，并非所有时钟都对这些结果同样敏感，并且取决于它们与实足年龄、健康寿命和寿命的潜在关系。某些时钟与相对短期的虚弱变化显着相关，从而支持它们在促进健康老龄化的倡议和干预中的效用。