IGF-1 (insulin-like growth factor-1) is a peptide hormone, produced predominantly by the liver in response to pituitary GH (growth hormone). IGF-1 is involved in a wide variety of physiological processes. In adults, IGF-1 has metabolic and anabolic effects, and it mediates many of the effects of GH.[2-4]
GH and IGF-1 levels are reduced with normal aging, a phenomenon called somatopause.[5-7] It has been suggested that somatopause is an age-related GH deficiency state. Somatopause has been considered to contribute to physiological deterioration seen with aging, like reduced muscle mass, reduced exercise tolerance, decreased strength, osteoporosis, increased fat mass, elevated cardiovascular risk, impaired quality of life, cognitive/memory decline and reduced immunity.[7-12] These changes are similar to those seen in classic (non-aging related) GH deficiency (GHD).[13, 14]
Consequences of high and low levels of GH and IGF-1
It is well-documented that abnormally high levels of IGF-1, seen in acromegaly, are associated with higher mortality and a higher prevalence of cancer and cardiovascular disease. And vice versa, in hypopituitarism, abnormally low levels of IGF-1 have been implicated to be responsible for high all-cause and cardiovascular mortality.
Associations of IGF-1 level within the normal range with disease are less clear. IGF-I has been suggested to promote atherosclerosis. Low-normal IGF-1 levels have been shown to be associated with development of heart disease and stroke [17-20] and higher circulating IGF-1 bioactivity is better associated with overall survival. Men in the lowest IGF-1 bioactivity had an almost 2-fold increased mortality risk compared with men with the highest IGF-1 bioactivity. In contrast, high-normal levels of IGF-1 have been reported to be associated with an increased risk of cancer.[22-27]
In humans, data on IGF-1 levels and longevity are conflicting.[28, 29] Decreased [30, 31] as well as increased  levels have been shown to be associated with reduced life expectancy in humans.
U-shaped relationship between IGF-I and mortality
If low IGF-1 levels are associated with an increased risk of developing cardiovascular disease and high IGF-1 levels are associated with an increased risk of developing cancer, there might be an optimal set point for the GH/IGF-1 axis associated with increased longevity. In line with this, several studies suggest an U-shaped relationship between IGF-I and mortality.[32, 33]
A notable study investigated the relationship between IGF-1 levels and all-cause/cause-specific mortality, cardiovascular disease and cancer, in a national representative sample of community-dwelling older persons over 65 years of age. After a follow-up of 11.6 years and after adjustments for confounders (age, sex, BMI, smoking, alcohol use, diabetes, physical activity, and albumin), the results demonstrated a 28% increased risk of all-cause mortality with IGF-1 values in the lowest quintile (7.3 nmol/L) as compared to the middle quintile (13.5 nmol/L). The risk of all-cause mortality for persons with IGF-1 levels in the highest quintile (21.4 nmol/L) was increased by 17%. A more than 2-fold increased risk of cardiovascular mortality was found for both low-normal (239% increased risk) and high-normal (203 % increased risk) IGF-1 levels. This study found no significant associations were found between IGF-1 levels and nonfatal cardiovascular disease and fatal and nonfatal cancer.
The decline of GH and IGF-1 levels with aging, aka somatopause, contributes to physical deterioration and increases mortality risk. It is interesting that having low-normal IGF-1 levels impose a greater risk of all-cause mortality and cardiovascular mortality than having high-normal IGF-1 levels. However, too high levels have been associated with cancer risk, which is important to bear in mind when undergoing GH (or IGF-1) therapy.
Because there is a U-shaped relationship between IGF-I level and mortality, if you are eligible for and consider GH therapy, it is advisable to aim for IGF-1 levels in the mid-normal range.
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