Learning from Laron Syndrome – Fight Aging!
The longest lived mice are still those engineered to lack functional growth hormone or growth hormone receptor. That record was established more than 20 years ago, and remains in place even as an energetic research and development community focused on treating aging as a medical condition has come into being. In part this is the case because research has largely focused on approaches known to produce lesser effects on aging in mice, such as the discovery of small molecules that mimic portions of the calorie restriction response. In part it is because the pace of development in the life sciences is ever slower than we would like it to be.
There are human practitioners of calorie restriction, and clinical trials have been conducted. This is how we know that calorie restriction in mice, largely operating through upregulation of autophagy, produces much larger effects on life span than is the case in humans. In the same way, there are humans who lack functional growth hormone or growth hormone receptor, the largest population of which exhibit Laron syndrome. Preliminary studies suggest that Laron syndrome provides some protection against cancer and metabolic disease, but there is no indication of extended life spans. So again the effect is small in humans in comparison to large in mice.
The consensus view on why this is the case is that humans are already fairly optimized for longevity, at least within the mammalian paradigm for cell and tissue biochemistry, or the parts of it most affected by calorie restriction and growth hormone metabolism. Our evolutionary history has been one in which we departed from our fellow primates in intelligence and sociology, leading to selection pressure for longer lives due to the ability of elders to help their descendants achieve reproductive success. Still, what about the rest of our biology? One of the most interesting questions in the field of aging research is how therapies to slow or reverse aging will differ in their performance between mice and humans once we depart from manipulation of growth-related metabolism to instead target the causes of aging, such as via clearance of senescent cells.
Insulin-like growth factors and aging: lessons from Laron syndrome
Pituitary-derived growth hormone (GH) along with insulin-like growth factor-1 (IGF1) constitute an endocrine axis with critical roles in growth and development. IGF1 is evolutionarily and structurally related to insulin. IGF1 production continues to be dependent on hypophysial GH secretion throughout all stages of life. Aging is linked to various endocrine deficits. In the specific context of the somatotrophic axis, GH and IGF1 biosynthesis progressively decrease as we age due to reduced activity of the hypothalamic GH releasing hormone (GHRH)-GH neuroendocrine system. Thus, while maximal GH and IGF1 levels are reached at mid-puberty, concentrations around the eight decade of life become drastically reduced. Indeed, both the amplitude of the GH secretory pulses as well as the basal levels between pulses are largely decreased. Reduction of endocrine GH levels is closely followed by a parallel decline in circulating IGF1.
Evidence has accumulated in recent years demonstrating that disturbance of the GH-IGF1 network correlates with prolonged lifespan in a number of animal species, including flies (D. melanogaster), nematodes (C. elegans) and mouse (M. musculus). Male mice harboring a disrupted GH receptor (GHR) gene (‘Laron’ mice) survive 55% longer than wild-type animals whereas female Laron mice have a 38% longer lifespan. The cellular and biochemical mechanisms that are responsible for the association between abrogation of the GH-IGF1 axis and prolonged lifespan are complex. Briefly, these mechanisms are functionally linked to the physiological role played by these hormones in nutrient sensing. Of relevance, whereas the effect of individual mutations on lifespan and health span in humans is usually difficult to assess, genomic analyses identified several differentially-represented aging-associated genes in Laron syndrome (LS) patients.
Epidemiological analyses have shown that patients with LS, the best-characterized disease under the umbrella of the congenital IGF1 deficiencies, seem to be protected from cancer. While aging and cancer, as a rule, are considered diametrically opposite processes, modern lines of evidence reinforce the notion that aging and cancer might, as a matter of fact, be regarded as divergent manifestations of identical biochemical and cellular underlying processes. While the effect of individual mutations on lifespan and health span is very difficult to assess, genome-wide screenings identified a number of differentially represented aging- and longevity-associated genes in patients with LS. The present review summarizes recent data that emerged from comprehensive analyses of LS patients and portrays a number of previously unrecognized targets for GH-IGF1 action. Our article sheds light on complex aging and longevity processes, with a particular emphasis on the role of the GH-IGF1 network in these mechanisms.
