The lifespan extension effect by GHR-KO doesn't translate to humans

#1

As we know, GHR-KO dwarf mice exhibit 40% longer lifespan.

Surprisingly, however, people with laron syndrome do not seem to live longer compared with their compatriots despite they are immune to cancer and diabetes.

How can we interpret this?

Studies suggest that people with Laron syndrome have a significantly reduced risk of
cancer and type 2 diabetes. Affected individuals appear to develop these common
diseases much less frequently than their unaffected relatives, despite having obesity (a
risk factor for both cancer and type 2 diabetes). However, people with Laron syndrome
do not seem to have an increased lifespan compared with their unaffected relatives

Once diagnosed in early childhood and severe hypoglycemia is prevented as well as diabetes adequately treated in later life, patients with Laron syndrome have a normal lifespan.

https://www.science.org/doi/10.1126/scitranslmed.3001845

Although it is difficult to prove that alterations in IGF-1 amounts are responsible for the cancer- and diabetes-free lives of these Ecuadorian people, genetic work from several model organisms suggests that this is so. In yeast, mutations in genes that encode components of a growth-promoting pathway protect against age-dependent genomic instability, and mutations in the insulin/IGF-1–like signaling pathway increase life span and reduce abnormal cellular proliferation in worms. Mice with defects in GH and IGF-1 live exceptionally long lives, with delayed appearance of age-dependent mutations and cancer. The Ecuadorians do not live longer-than-normal lives compared with their compatriots, but rather die in due course from causes of death other than cancer and diabetes complications. Thus, the metabolic inverse of “live fast and die young”—a slowed metabolism yields a longer life—is not supported by the current findings. But a life free from two dreaded diseases may be considered a desirable trade-off.

The GHRD cohort shows high mortality from common diseases of childhood(Fig. 1F) (41). Because of this, we considered only individuals who survived to at least age 10 for further analysis of diseases in this cohort. Of the 30 deaths among GHRD subjects (data from both monitoring and surveys) older than 10, 9 were due to age-related diseases (8 from cardiac disease, 1 stroke) and 21 were due to non–age related causes. Compared to their relatives, GHRD subjects died much more frequently from accidents, alcohol-related causes, and convulsive disorders (Fig. 2A).

Although GHRD subjects may have elevated cardiac disease mortality (Fig. 2A), the mortality from vascular diseases (combining cardiac disease and stroke) appears to be similar to that of their relatives (33% of deaths in relatives versus 30% of deaths in GHRD subjects) (Fig. 2A). In agreement with studies of a human population with isolated GH deficiency (45), our data suggest that GHRD does not increase overall vascular disease mortality (Fig. 2A).

Unlike model organisms with similar mutations, human GHRD subjects did not live longer lives. The lack of life-span extension in GHRD subjects may be explained in large part by the high proportion of deaths (70%) caused by convulsive disorders, alcohol toxicity, accidents, liver cirrhosis, and other non–age-related causes. The lack of cancer mortality and normal life span in GHRD subjects is in agreement with a preliminary study that reported the absence of cancer in a group of 222 patients with congenital IGF-1 deficiencies (61) and with the normal life span that was observed in 65 GH-deficient subjects (45). In contrast to our study of GHRD subjects with specific mutations and their age-matched relatives, Shevah and Laron (61) compared young subjects with IGF-1 deficiencies due to many causes with much older controls, which made it difficult to determine whether cancer incidence was reduced. However, together, these two studies provide strong evidence for reduced cancer incidence in GHR- and IGF-1–deficient subjects and indicate that GHR and IGF-1 are risk factors for age-dependent cancer, at least in specific populations. Our results may also provide a partial explanation for the overrepresentation of partial loss of-function mutations in the IGF-1R gene among Ashkenazi Jewish centenarians

3 Likes
#2

Maybe the downside of having no growth hormone is fraily or increased susceptibility to infections? Inhibiting it in normal adult rats also does not seem to have a lifespan extending effect, making me wonder whether inhibiting growth hormone (contionuously) does have any effect on lifespan at all.

#3

I think its valuable to look at why these people (the adults) with Laron Syndrome actually die. Its a very small sample size so you have to be careful about broad generalizations (there are only 100 or so of these people in Ecuador and perhaps 250 people globally).

In this reference the commenter suggests:

It looks like 20% die from accidents vs 2% of their relatives, 17% from convulsive disorders [such as epilepsy] and 13% from alcohol related deaths.

Perhaps they would live longer, much longer, if they didn’t live in the off-grid rural hills towns of Ecuador, and instead lived in a place with lower accident risk and less alcohol?

http://stm.sciencemag.org/content/3/70/70ra13.full.html

The Ecuadorian Laron population studied by Longo “shows high mortality
from common diseases of childhood”; those that survive to age 30 “died much more frequently [than non-mutant relatives used as controls] from accidents, alcohol-related causes, and convulsive disorders [such as epilepsy]”.

5 Likes
#4

And, of course, anything we do to lower GH later in life is going to be a very different experiment than what the Laron Syndrome people experience (with their lower GH from conception)… so our results would be much less (than their already mediocre lifespan benefit).

There is evidence that most of the benefit of the lower growth hormone accrues only if GH is low during a brief period of early life (i.e. in the first few weeks or months of life) - as I mentioned in this post: Age1 Venture Capital Launches New Youtube Channel on Longevity & Biotech - #17 by RapAdmin

And generally, as Invivo mentioned in this post, the data is pretty sparse, though there have been some positive later life studies: Age1 Venture Capital Launches New Youtube Channel on Longevity & Biotech - #25 by invivo

So generally, I think lower GH may be beneficial for disease prevention, but as a later-life intervention for humans it seems less promising for lifespan improvement.

1 Like
#5

But also not all mice live longer with GH KO lifespan mutation - there were tried many GH KO mutations lifespan experiments in mice - it extended lifespan in some experiments and didn’t in other - it depends on specific gene mutation - not every mutation that lowers GH extended lifespan in mice

#6

The same thing could be said of testosterone earlier in males lifes but as we age TRT improves health and many of the markers we link positively with good health. Same with GH. If GH pulse are restored via upstream signaling using peptides (as oposed to direct gh injections which chronically elevates plasma gh) you get similar positive health effects. Chronically elevated in most things is not ideal.