A few years back, researchers noted that a common growth hormone receptor gene variant was associated with greater life expectancy in humans. There was some theorizing as to possible mechanisms at the time, following the usual paths for anything that touches on growth hormone or its receptor. In short-lived mammals such as mice, loss of function in growth hormone or its receptor produces small body size and increased healthy longevity. The present record for mouse longevity is held by a growth hormone receptor knockout lineage. In humans, members of the small Laron syndrome population exhibit an analogous disruption of growth hormone metabolism, and while there are signs that they might be more resistant to some forms of age-related disease, they do not live notably longer than the rest of us. It is usually the case that metabolic alterations of this nature, in this part of metabolism, have large effects in short-lived species and much smaller effects in long-lived species.
Given the example of Laron syndome to suggest that the usual explanations regarding growth hormone metabolism may not be useful here, how might variants in the growth hormone receptor gene actually produce an effect on human longevity? Researchers have been working to answer that question, and in today's open access paper it is proposed that some variants reduce the negative impacts of raised blood pressure, or hypertension. Blood pressure is very influential on health and mortality in later life. Raised blood pressure causes damage to delicate tissues in organs throughout the body, and particularly in the brain. It also accelerates the progression of atherosclerosis, and makes it more likely that atherosclerotic vessels burst or become blocked. It also contributes to heart failure. Hypertension causes so many forms of downstream damage that control of raised blood pressure via current standards of medication, approaches that in no way address the underlying causes of the condition, can nonetheless reduce mortality risk by a sizable amount.
Growth hormone (GH) and its receptor (GHR) are not only important for regulating growth, they have many other important biological functions including response to nutrients, regulation of metabolism, and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. Growth hormone signaling is an important regulator of aging. GH deficiency leads to slower growth, delayed maturation, reduced body size, and can result in attenuation of the rate of aging, increased health-span, and increased longevity. Key to this are evolutionarily conserved pathways of insulin/insulin-like growth factors and mechanistic target of rapamycin, where there are trade-offs between anabolic processes/growth and lifespan.
We have reported a significant negative association between height and longevity in our large cohort of American men of Japanese ancestry. More recently, in a case-control study of 13 single nucleotide polymorphisms (SNPs) of GHR in this cohort, SNP rs4130113 was associated with greater lifespan of nonagenarian men aged ≥ 95 years. In the present longitudinal study, we tested the hypothesis that genetic variation in GHR affects lifespan at least in part by protection against the detrimental effects of one or more aging-related diseases, namely diabetes, hypertension, coronary heart disease, and/or cancer.
The present study has found that the longevity-associated AA genotype (frequency 35.3%), but also the GG genotype (frequency 17.1%), of GHR SNP rs4130113 is associated with protection against risk of mortality in hypertensive elderly American men of Japanese ancestry. As a result, those individuals lived longer, whereas individuals with the AG genotype (frequency 47.6%) died sooner. Moreover, the survival curve for hypertensive AA/GG subjects did not differ significantly from the survival curve for normotensive subjects with the AA/GG genotype. This indicated that possession of the GHR longevity-associated genotype can mitigate the adverse effects on lifespan of having hypertension.