Augmenting Growth Hormone for Better Aging: Is It a Good or Bad Idea?
In our previous article addressing aging, we discussed the mTOR pathway, and how metabolic processes that favor growth may not necessarily lead to better longevity.
Now, we are going to discuss growth hormone – a peptide hormone that stimulates cell growth and regeneration – and its role in the context of aging and longevity.
Growth hormone works primarily in two ways:
1) directly, by inducing protein synthesis
2) indirectly, by telling the liver to produce insulin-like growth factor 1 (IGF-1).
When we think of the term growth, we usually think of someone becoming taller. But growth is also important for tissue regeneration – which is necessary for the maintenance of stable tissue function even after adulthood is reached.
Together, both GH and IGF-1 help maintain muscle mass and bone density, while increasing fat metabolism. But the secretion of growth hormone declines drastically when we get older. By middle age, we have only 15% of the level that we had during puberty. Not surprisingly, IGF-1 levels follow a similar pattern over the years. Indeed, the reduction of both growth hormone and IGF-1 may explain, at least in part, the frailty and muscle loss associated with old age.
For this reason, injectable growth hormone at one time seemed like a promising method to reverse the aging process. In the 1990s, GH replacement seemed like a potential panacea, with promises that it would restore energy, sexual vigor, youthful skin, and even reverse graying hair. To this end, it has been estimated that somewhere between 20,000 and 100,000 Americans used GH as “anti-aging” therapy in 2004 alone.
Going back to my very first article in this series on better aging, the goal is not simply to live longer but to have health and vitality for a greater fraction of the lifespan. So, achieving better tissue regeneration and body composition is obviously very alluring.
Large clinical studies have revealed, indeed, there is a modest benefit for body composition. Frustratingly, these benefits were overshadowed by unacceptable side effects. For example, adults on GH replacement therapy may experience profound deterioration in glucose metabolism – which can eventually lead to diabetes.
So, did we get this all wrong? Instead, should we aim to suppress GH in order to live longer?
Lessons from Those with Altered GH / IGF-1 Signaling
Data on animals and humans with naturally altered GH and IGF-1 activity has some obvious limitations. It is likely that the cumulative exposure to certain hormones over an individual’s lifetime – as would be characteristic of certain gene mutations – results in somewhat different effects than in those who are replacing a diminished hormone later in life. But with that caveat in mind, let’s take a look at what insight those animal and human models offer us.
What Happens to Animals with Altered Growth Hormone?
Several different strains of mice don’t produce growth hormone or have impaired signaling in the GH pathway. Such mice tend to be obese and about 30% smaller, and are seemingly protected from diabetes and cancer. They also live 25-50% longer than their normal counterparts.
On the other hand, mice with excessive GH production are super lean giants, with significantly shortened lifespans. This premature mortality appears to be due to insulin resistance, and other pathological changes associated with chronically high growth hormone levels, including increased incidence of cancers.
What Happens to Humans with Altered Growth Hormone?
One interesting example is a group of people from the island of Krk in Croatia, who are deficient in GH and other pituitary hormones due to gene mutations. These people exhibit a number of interesting features, most of which one might predict based on the animal models. They are short and obese, with delayed appearance of gray hair. They are also resistant to diabetes and enjoy longer lifespans than the general population.
Similarly, people with Laron syndrome are naturally insensitive to GH as a result of mutations in the receptor. Adults with this condition are also small and obese, and they remain relatively free of cancer and diabetes throughout their lives.
The characteristics of these groups of people are remarkably similar to the mouse models described above, validating the usefulness of these relevant animal models for humans.
Finally, a prospective study done in a cohort of people from Leiden in the Netherlands analyzed the relationship between insulin and IGF-1 signaling and longevity over a 20-year period. Decreased IGF-1 activity was found to be associated with both reductions in body height and increases in old age survival.
Trade-Offs Between Reproductive Capacity and Longevity
One might wonder why we would evolve with hormones that make us die young in the first place?
A plausible explanation for this paradox is the notion of antagonistic pleiotropy. This hypothesis suggests that natural selection may favor genes that increase reproductive potential – even at the expense of long-term vitality and longevity.
The GH / IGF-I axis is most active around the time of puberty when it spurs growth and maintenance of muscle and bone mass, as well as the induction of sexual maturity. Early in life, this can confer significant advantages for reproduction. One might imagine that animals with reduced GH / IGF-1 activity would be relatively small and weak. They might struggle to compete with fitter peers for resources and mates. Consequently, those endowed with a more active GH / IGF-I axis are better able to reproduce, and the gene gets passed to subsequent generations.
When the animal gets older, however, that robust GH / IGF-I axis leaves them susceptible to insulin resistance and cancer. They die younger as a result – but only after they have already reproduced. Therefore, high growth hormone may be a double-edged sword from the standpoint of reproductive fitness and longevity.
In the second post on this subject, we will address lifestyle factors that can modify the activity and sensitivity of GH / IGF-1 axis for better aging. For example, caloric restriction has been shown to reduce IGF-1 concentrations. This suggests the possibility that the longevity effects of caloric restriction may be due, at least in part, to changes in the GH / IGF-1 signaling. We will also address whether other lifestyle factors – like fasting, ketosis, circadian rhythms – can play a significant role to modify this pathway for our benefit.