Endocrinology and Diabetes Research Unit, Schneider Children’s Medical Center of Israel, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Israel
Primary or secondary IGF1 deficiency has been implicated in shortening of lifespan. This paper reviews available data on the influence of IGF1 deficiency on lifespan and longevity in animals and man. It has been shown that inactivation of the IGF1 gene or of the GH receptor in both invertebrates (C-elegans, flies-Drosphila) and rodents (mice and rats), leading to IGF1 deficiency, prolong life, particularly in females. In man, evaluation of the 2 largest cohorts of patients with Laron syndrome (inactive GH receptor resulting in IGF1 deficiency) in Israel and Ecuador revealed that despite their dwarfism and marked obesity, patients are alive at the ages of 75-78 years, with some having reached even more advanced ages. It is assumed that a major contributing factor is their protection from cancer, a major cause of death in the general population.
Aging, GH deficiency, IGF1 deficiency, Insulin, Insulin sensitivity, Lifespan, Longevity
As the relationship between Growth Hormone Deficiency (GHD) and longevity is controversial,1,2 it is worth examining whether the paradigm of congenital IGF1 deficiency could contribute to clarification of this issue and resolve pertinent questions. Parallel with growth hormone, serum IGF1 decreases with age, reaching serum levels of 150 ng/ml at around age 50 and about 100 ng/ml at around age 80 years (Figure 1).3,4 In childhood onset GHD, the IGF1 values are lower than normal for age (Figure 1). The changes of paracrine IGF1 with advancing of age are unknown. The increase of cardiovascular disease with age is considered to be the major cause of non-traumatic death in the western world,5 shortening the normal lifespan. Cancer is another cause.6 Both types of diseases are also known to influence the lifespan in GH/IGF1 deficient patients. Below is an overview of the known facts.
Figure 1. Decrease of serum IGF1 levels with age. Dots represent levels in patients with childhood onset GH deficiency (with permission from Blum W4).
WHAT IS THE EVIDENCE THAT IGF1 INFLUENCES THE LIFESPAN?
Prolonged and/or increased IGF1 secretion
The example in man is acromegaly, which is characterized by increased levels of IGF1 and enhanced mortality via cardiovascular disease, diabetes and malignancy.7 The animal counterparts are GH-transgenic mice who have chronically elevated levels of GH in the peripheral circulation and consequently an increase in the production of IGF1.8 These mice have an increased incidence of mammary tumors9 and hepatomas10 which contribute to the shortened lifespan of the animals.10
Animal models have established the IGF1 signaling pathway as a key modulator of aging and longevity in invertebrates and rodents.
In the nematode “Caenorhabditis elegans”, mutants of daf-2, a homolog of the insulin/IGF1 tyrosine kinase receptor, live three times longer than the wild-type animals.11,12 Binding of the insulin/IGF1 ligand to daf-2 initiates a cascade leading to daf-16, a regulatory transcription factor. During starvation, deactivation of daf-2 and reduced daf-16 activity, a state of arrested development (dauer formation), fat accumulation and delayed reproduction result in increased lifespan. A similar process was shown in the fly “Drosophila melanogaster”.13
Inactivation of the Igf1r gene in mice14 revealed that null mutants are not viable, while heterozygous KO mice (Igf1r +/-) lived on average 26% longer than their wild-type litter mates, with female Igf1r +/- mice living longer than the male.14
Inactivation of the GHRH receptor gene
Missense mutations of the GHRH receptor gene in the lit/lit mice, which cause very low IGF1 levels, result in a prolongation of lifespan by 20-25%.15
Inactivation of the GH reseptor gene
Targeted disruption of the mouse growth hormone receptor/binding protein gene (GHR/BP KO-/-, the Laron mouse)16 resulted in dwarfism and an increased lifespan, most markedly in the female mice17 (Table 1 ). These mice that are similar to the human model18 have low IGF1 and high GH levels.
At present, there is only one model with sufficient adult patients to review this issue, namely Laron syndrome (LS, primary GH insensitivity or resistance), a recessively inherited syndrome caused by deletions or mutations in the GH receptor or post-receptor pathways.18 Due to the clinical unavailability of IGF1, which constitutes their only treatment, it has been possible to evaluate the lifespan and morbidity in a sizeable number of untreated patients. The consequences of long-term IGF1 deficiency are: dwarfism, progressive and marked obesity,19 hyperlipidemia,20 relative insulin resistance21 and even Type 2 diabetes with its vascular complications in some patients after age 40.18,22
There are two large cohorts of patients with Laron syndrome in which longevity data are available: a) the Israeli cohort numbering at present 65 patients and followed up by our group since 1958,18 and b) the Ecuadorian cohort estimated at 135 patients.23,24
a) The Israeli cohort of Laron syndrome patients
Out of the 65 LS patients, some are children, a number of whom have been treated with IGF1.25 We have registered 2 deaths: one girl in infancy probably due to hypoglycemia and one 78-year old male patient by road accident. The untreated adult patients whom we now monitor range in age from 25 to 60. Almost all the patients of this cohort are of Jewish Oriental, Arab and Mediterranean origin.
b) The Ecuadorian cohort (LS-E)
Recently compiled data24 revealed 75 living patients, the oldest recorded aged 76 years. Six patients of the originally recorded cohort23 have died, five of myocardial infarction and one in an accident. The age was not specified. Twenty-two children with LS-E have died at an early age, apparently from infections and/or hypoglycemia.24 Most of the Ecuadorian patients live among or originate from isolates in the mountains in the southern region of Loja in Ecuador.26
Several animal models definitely prove that congenital IGF1 deficiency prolongs lifespan, especially in females.11-17 These animals have, in addition to low IGF1, reduced insulin and glucose levels.27 Caloric restriction has also been proposed as playing an important role.28
In the Laron syndrome patients, ages of up to 76 and 78 have been recorded. Our patients with hypercholesterolemia are being successfully treated with statins, while the patients with Type 2 diabetes and cardiovascular disorder are now at age 55 years despite erratic diabetes control. The second patient with diabetes and complications died in a road accident. Our 56-year old female subject with glucose intolerance is currently under treatment.
Detailed data on the Ecuador cohort and patients from other countries18,29 are missing.
Despite reports of death at an early age among patients with isolated GH deficiency2 as well as those with hypopituitarism,30,31 untreated patients with congenital isolated IGF1 deficiency seem to reach old age despite marked obesity, development of hyperlipidemia and a tendency to develop diabetes and its complications.
The possible reasons are:
Laron syndrome patients are protected from development of cancer;32
They have relatively low insulin levels relative to their degree of obesity;
The hyperlipidemia, glucose intolerance, diabetes and cardiac states are nowadays treatable.
In conclusion, lifelong IGF1 deficiency permits ageing and does not shorten lifespan, possibly even prolonging it, one major reason being that these patients are protected from cancer, a major cause of death in the general population.
There is an isolated village called Vilcabamba situated in the mountains about 40 km from the city of Loja in Ecuador which has long been renowned for the remarkable longevity of its inhabitants, who attain lifespans of 85 and up to and even over 100 years.33 We are at present carrying out research as to whether there is any genetic link between these long-living people and the Laron syndrome patients in Loja.
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Address for correspondence: Professor Z. Laron, MD, Endocrinology and Diabetes
Research Unit, Schneider Children’s Medical Center of Israel,
Petah Tikva 49202, Israel, Tel. 972-3-9253610/1;
Fax 972-3-9222996; e-mail: firstname.lastname@example.org
Received 17-09-07, Revised 15-10-07, Accepted 10-11-07