The average lifespan of a human ranges from ~65 to 85 years, and the frequency of centenarians is 1 in 10,000 worldwide (1). In studies conducted on twins, human longevity has been indicated to be moderately heritable, and different genetic mutations account for ~25% of human longevity (2). Although studies have been performed to evaluate the role of genetic mutations in human longevity, only the apolipoprotein E (APOE) gene has been analyzed in several populations (3, 4). Following the discovery of the association between APOE gene and human longevity, lipid metabolism has become the most studied pathway; however, there is some evidence that human longevity is associated with an increased resistance to oxidative stress (5). Chen and colleagues have reported the relationship of centenarian longevity with single nucleotide polymorphism (SNP) rs189037 of the ataxia-telangiectasia mutated (ATM) gene (6). The protein encoded by ATM gene is resistant to oxidative stress owing to its role in the detection of reactive oxygen species (ROS)-induced lesions and repair of DNA defects (7, 8). ROS is now considered to contribute to senescence primarily by inducing DNA double-strand breaks (DSBs) and causing telomere dysfunction (9). ATM gene detects DNA damage and phosphorylates and activates downstream kinases, such as checkpoint kinases ChK1 and ChK2 and P53 (10). Moreover, an antioxidant system exists, which can reduce ROS levels. ATM gene plays a crucial role in balancing redox state, and it is widely expressed in many tissues, including the brain, skin, and endothelial cells (11). ATM expression and function are markedly decreased in aged mice. Patients with mutations in ATM gene present with insulin resistance, growth retardation, immune deficiency, and increased susceptibility to cancer. These observations suggest that ATM is critical to human lifespan (12). Studies have investigated the association between mutations in ATM gene and exceptional human longevity, but to the best of our knowledge, no studies have been conducted to assess the influence of the gene across human lifespan (6). The genetic basis for influencing human lifespan could improve the understanding of aging mechanisms, thus providing new insights and targets to avoid structural abnormality and promote successful aging. An abnormal cardiac structure is responsible for increased mortality rates and a significant obstacle in improving human longevity. At present, studies on SNPs in ATM gene have primarily focused on cancer and lifespan, and limited information regarding the specific effects of mutant rs189037 in ATM gene on cardiac structure and human longevity is available. In the current study, we aimed to determine the association of SNP rs189037 in ATM gene with cardiac structure and human longevity.

Table 1 describes the basic characteristics and genotype distribution of SNP rs189037 in young, middle-aged and elderly, and centenarian participants. The frequency of TT genotype was significantly higher and that of CC genotype was significantly lower in middle-aged and elderly participants than in young (P = 0.012) and centenarian (P = 0.041) participants. C allele in middle-aged and elderly participants was significantly less frequent compared with young (P = 0.005) and centenarian (P = 0.019) participants. There were no significant differences in the genotype and allele frequencies of SNP rs189037 between young and centenarian participants. Distributions of genotype frequencies in young (P = 0.232), middle-aged and elderly (P = 0.471), and centenarian (P = 0.982) participants were compatible with the Hardy-Weinberg equilibrium (P > 0.05).

Table 2 shows the multiple associations of age groups with different genotypes of SNP rs189037. Compared with CC genotype, TT genotype was positively and significantly associated with middle-aged and elderly/young participants [Exp(B) (95% CI): 3.303 (1.107–9.859); P = 0.032]. The genotypes of SNP rs189037 were not significantly associated with centenarian/young participants.

The basic characteristics of centenarians with different genotypes of SNP rs189037 are presented in Table 3. Centenarians with TT and CT genotypes showed significant differences in left ventricular posterior wall thickness (LVPWT; P = 0.004). Centenarians with TT and CC genotypes showed significant differences in LVPWT (P = 0.047; Figures 1E,G,H). Centenarians with CT and CC genotypes showed significant differences in LVEDD (P = 0.008).

Table 4 shows multiple associations of cardiac structure and function with different genotypes of SNP rs189037 in centenarians. Compared with CT genotype, TT genotype was positively and significantly associated with IVS [Exp(B) (95% CI): 1.181 (1.001–1.394); P = 0.049] and LVPWT [Exp(B) (95% CI): 1.152 (1.002–1.324); P = 0.047] in centenarians. Compared with CC genotype, TT genotype was positively and significantly associated with LVPWT [Exp(B) (95% CI): 1.244 (1.021–1.517); P = 0.030] in centenarians. Compared with CC genotype, CT genotype was negatively and significantly associated with LVEDD [Exp(B) (95% CI): 0.947 (0.908–0.988); P = 0.011] and positively and significantly associated with RVEDD [Exp(B) (95% CI): 1.064 (1.009–1.123); P = 0.022] in centenarians.

The basic characteristics of middle-aged and elderly participants with different genotypes of SNP rs189037 are presented in Table 5. Middle-aged and elderly participants with TT and CT genotypes showed significant differences in LVPWT (P = 0.037), LVEDD (P = 0.015), and left ventricular ejection fraction (LVEF, P = 0.032). Middle-aged and elderly participants with TT and CC genotypes showed significant differences in LVPWT (P = 0.043; Figures 1F,I,J).

Table 6 shows multiple associations of cardiac structure and function with different genotypes of SNP rs189037 in middle-aged and elderly participants. Compared with CT genotype, TT genotype was positively and significantly associated with IVST [Exp(B) (95% CI): 1.739 (1.156–2.615); P = 0.008], LVPWT [Exp(B) (95% CI): 2.016 (1.244–3.267); P = 0.004], and LVEDD [Exp(B) (95% CI): 1.207 (1.070–1.361); P = 0.002] in middle-aged and elderly participants. Compared with CC genotype, TT genotype was positively and significantly associated with IVST [Exp(B) (95% CI): 1.801 (1.141–2.843); P = 0.012] and LVPWT [Exp(B) (95% CI): 1.925 (1.145–3.236); P = 0.013] in middle-aged and elderly participants. Compared with CC genotype, CT genotype was negatively and significantly associated with LVEDD [Exp(B) (95% CI): 0.909 (0.829–0.996); P = 0.040] in middle-aged and elderly participants.

In middle-aged and elderly and centenarian participants, the current study demonstrated that CT genotype of SNP rs189037 was significantly associated with reduced LVEDD, while TT genotype was significantly associated with increased IVST, LVPWT, and LVEDD. For SNP rs189037 in ATM gene, heterozygous mutation might result in LV concentric development, whereas homozygous mutation might further induce LV eccentric hypertrophy. Moreover, the frequency of TT genotype was similar between young and centenarian participants; however, middle-aged and elderly participants showed significantly higher frequency of TT genotype. SNP rs189037 without mutation might be an indicator of youth health and successful aging, whereas mutant rs189037 might hinder successful aging and human longevity.

Human lifespan is the outcome of multiple processes involving genetic factors; thus, several genetic studies have investigated putative associations between genes and longevity, but to the best of our knowledge, no studies have been conducted to assess the influence of the genes across human lifespan. The current study identified SNP rs189037 without mutation as a biomarker of youth health and successful aging by analyzing genotypic change in ATM across human lifespan. ROS can lead to DSBs and telomere dysfunction, which are critical causes of DNA lesions (8). Once DNA lesions occur, the protein encoded by ATM gene phosphorylates numerous downstream effectors involved in the G1/S, intra-S, and G2/M checkpoint responses and additional factors involved in DNA repair, including tumor suppressor proteins P53, ChK1, and ChK2 (10). Therefore, ATM mutations possibly make individuals susceptible to cancer and are harmful for physiological activity. This suggests that ATM gene plays a significant role in prolonging human lifespan.

Accumulating evidence has illustrated that SNPs in gene regulate gene expression, and people with different SNPs show distinct phenotypes (16, 17). A previous study has shown the presence of an AP-2a-binding site around SNP rs189037 in ATM gene, which is a transcriptional factor involved in both physiological and pathological processes, such as tumorigenesis and morphogenesis (18). It has been verified in human cells that TT genotype of SNP rs189037 increases ATM mRNA expression, and AP-2a represses ATM expression in humans by binding to CC genotype (6). It is also believed that balance exists in every activity of the physiological process; mutant SNP in gene alters protein phenotypes, disrupts physiological balance, and causes pathological changes. For example, mutant SNP rs189037 in ATM gene or consistently high activity of P53 results in abnormal cardiac structure or premature senescence of individuals (19). The current study reported that SNP rs189037 without mutation might prevent the development of an abnormal cardiac structure and death at an early age; hence, it is not only an indicator and biomarker of youth health and successful aging but also promotes successful aging and prolongs human lifespan.

Aging is a complicated process affected by several genetic and non-genetic factors (1). Genes are the predominant factors responsible for aging, and SNPs associated with aging might exist. Mice with deficient ATM gene have been shown to experience accelerated aging (20). As a regulator of oxidative stress and sensor of DNA damage, ATM gene prevents cellular senescence, death, or cell cycle arrest; in addition, it protects individuals from ROS-induced DNA damage. Ding et al. have described an association of SNP rs189037 in ATM gene with the proportion of coronary artery disease in Chinese Han population and demonstrated a low proportion of coronary artery disease in participants harboring TT genotype (21). In the current study, the young and centenarian participants showed significantly lower frequency of mutant rs189037 in ATM gene than middle-aged and elderly participants. Individuals without mutant rs189037 in ATM gene may age later and live long, and reversing mutant rs189037 might be a suitable strategy to delay human aging and promote human longevity.

The current study demonstrated that mutant SNP rs189037 in ATM gene was more commonly identified in the middle-aged and elderly participants than in young participants and centenarians. It was significantly associated with increased LV thickness and volume and might induce LV eccentric hypertrophy and shorten human lifespan.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Ethics Committee of the Hainan Hospital of the Chinese People's Liberation Army General Hospital (Sanya, Hainan; No: 301hn11201601). The patients/participants provided their written informed consent to participate in this study.

SF, JH, XC, BL, HS, JD, YJZ, YY, and YLZ contributed to the study design, conducted the data collection and analyses, and drafted the paper. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.