Supplementary Material for: Programmed Cell Death Genes Are Linked to Elevated Creatine Kinase Levels in Unhealthy Male Nonagenarians

Declining health in the oldest-old takes an energy toll for the simple maintenance of body functions. The underlying mechanisms, however, differ in males and females. In females, the declines are explained by loss of muscle mass; but this is not the case in males, in whom they are associated with increased levels of circulating creatine kinase. This relationship raises the possibility that muscle damage rather than muscle loss is the cause of the increased energy demands of unhealthy aging in males. We have now examined factors that contribute to the increase in creatine kinase. Much of it (60%) can be explained by a history of cardiac problems and lower kidney function, while being mitigated by moderate physical activity, reinforcing the notion that tissue damage is a likely source. In a search for genetic risk factors associated with elevated creatine kinase, the Ku70 gene <i>XRCC6</i> and the ceramide synthase gene <i>LASS1</i> were investigated because of their roles in telomere length and longevity and healthy aging, respectively. Single nucleotide polymorphisms in these two genes were independently associated with creatine kinase levels. The <i>XRCC6</i> variant was epistatic to one of the <i>LASS1</i> variants but not to the other. These gene variants have potential regulatory activity. Ku70 is an inhibitor of the proapoptotic Bax, while the product of Lass1, ceramide, operates in both caspase-dependent and -independent pathways of programmed cell death, providing a potential cellular mechanism for the effects of these genes on tissue damage and circulating creatine kinase.

高龄老人的健康衰退会为维持身体基础生理功能带来额外的能量消耗负担。然而，其背后的潜在作用机制存在性别差异。对于女性而言，健康衰退可归因于骨骼肌量流失；但男性的情况并非如此，其健康衰退与循环肌酸激酶（circulating creatine kinase）水平升高相关。这一关联提示，导致男性不健康衰老过程中能量需求升高的原因或许是肌肉损伤，而非骨骼肌量流失。本研究现已对肌酸激酶水平升高的相关影响因素展开了探究。其中约60%的水平升高可通过心脏病史与肾功能减退加以解释，而适度体力活动可缓解这一升高，进一步佐证了组织损伤是其潜在诱因这一观点。为寻找与肌酸激酶水平升高相关的遗传风险因素，本研究针对Ku70基因（<i>XRCC6</i>）与神经酰胺合酶基因（<i>LASS1</i>）展开了分析——二者分别在端粒长度调控、寿命维持以及健康衰老过程中发挥作用。这两个基因的单核苷酸多态性（single nucleotide polymorphisms）与肌酸激酶水平分别存在独立关联。<i>XRCC6</i>基因的变异体与其中一个<i>LASS1</i>基因变异体存在上位性关联，但与另一个<i>LASS1</i>变异体则无此关联。上述基因变异体均具备潜在的调控活性。Ku70是促凋亡蛋白Bax的抑制剂，而Lass1的表达产物神经酰胺则可同时参与半胱天冬氨酸蛋白酶（caspase）依赖与非依赖的程序性细胞死亡通路，为上述基因通过影响组织损伤与循环肌酸激酶水平发挥作用提供了潜在的细胞机制。