The role of the IGF-1 system in modulating longevity: contradictions and new understanding in terms of centenarians
Human aging is currently defined as the physiological decline of biological functions in the body with constant adaptation to internal and external damage. The endocrine system plays an important role in the organization of cellular interactions, metabolism, growth and aging. Several studies, from worms to mice, have shown that suppressing the activity of the growth hormone / insulin-like growth factor-1 / insulin (GH / IGF-1 / insulin) can be useful for extending a person’s longevity, while the results are contradictory in humans. In this review, we discuss the potential role of the IGF-1 system in modulating longevity, hypothesizing that the endocrine and metabolic adaptations observed in centenarians and mammals with calorie restriction may be a physiological strategy for increasing longevity due to slower cell growth / metabolism, better utilization of physiological reserves, a shift in cellular metabolism from cell proliferation to regenerative actions and a decrease in the accumulation of senescent cells.
Introduction.
Aging is defined as the physiological decline of biological functions in the body with a progressive decrease or loss of adaptation to internal and external damage. In humans, the aging phenotype is extremely heterogeneous and can be described as a complex mosaic resulting from the interaction of several random and environmental events, genetic and epigenetic changes accumulated over a lifetime. Despite its enormous complexity, the molecular basis of aging is limited to the few highly evolutionarily conservative biological mechanisms responsible for maintaining and restoring the body (1).
In the past 3 decades, one of the most discussed topics in gerontology is the role of the growth hormone (GH) / insulin-like growth factor-1 (IGF-1) / insulin system in the regulation of longevity. Accumulated evidence suggests that this pathway plays an important role in the pathogenesis of a number of age-related diseases, including cancer, dementia, cardiovascular and metabolic diseases (2–4).
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In animal models, it has been shown that the suppression of the GH / IGF-1 / insulin system significantly increases life expectancy. However, data is contradictory in humans (5, 6).
This review describes recent advances in the study of the IGF-1 system and modulation of longevity, hypothesizing that the endocrine and metabolic adaptations observed in centenarians and mammals during calorie restriction may be a physiological strategy for increasing longevity due to slower cell growth / metabolism, better control of signal transduction and physiological reserve power and reduced accumulation of aging cells.
Figure 1 Pleiotropic effect of IGF-1 on the body. On one side of the scale, which outweighs: tissue homeostasis, cardioprotective and neuroprotective effects, insulin-like effects, participation in the formation of the skeleton and muscle regeneration. On the second scale: the risk of carcinogenesis.
The IGF-1 system has several pleiotropic effects on biological aging (see figure 1). IGF-1 plays an important role in fetal development, growth in childhood and adolescence, and adult tissue homeostasis. In addition, IGF-1, apparently, has atheroprotective action, neural protective and insulin-like action (in high concentrations), regulates bone metabolism and muscle regeneration. However, IGF-1 is a major risk factor in the development of several types of tumors due to its strong proliferative activity, mainly due to modulation of the cell cycle, apoptosis and cell survival (7-9). Most of these effects are mediated by interaction with the insulin receptor substrate (IRS) -1 and-2 and modulation of the mammalian PI3K / AKT pathway / target of rapamycin in mammals (mTOR) (see Figure 2)
Fig.2 Schematic representation of several components of the IGF-1 / PI3K / AKT / mTOR path, discussed in this review. IGF-1 increases AKT activity with corresponding effects on cell survival and proliferation, glucose metabolism and protein synthesis.
Several preclinical studies have reported that mutations in the genes controlling the GH / IGF-1 / insulin signaling pathway can significantly increase life expectancy in both invertebrate and vertebrate animal models (5, 6).
Invertebrate models.
In the invertebrate, the insulin / IGF-like cascade is regulated by several peptides capable of interacting with one common insulin / IGF-1-like receptor.
In the nematode Caenorhabditis elegans, insulin / IGF-like pathway consists of several proteins encoded by the genes daf-2, age-1 (encoding the catalytic subunit PI3K), akt-1, akt-2, pdk-1, sgk-1 (serine-threonine kinase ), daf-16, skn-1 and daf-18 (PTEN, phosphatase, involved in the inhibition of the AKT signaling pathway). The reduced activity of the daf-2, age-1, akt-1, akt-2, pdk-1, sgk-1 genes suppressed this path, and animals with these mutations have been reported to age more slowly and have an increased lifespan. up to 300%. In contrast, stimulation of the insulin / IGF-like pathway reduces the lifespan of nematodes (10, 11).
In the Drosophila melanogaster fruit fly, insulin-like / IGF-like signaling consists of dINR (a protein similar to insulin receptor / IGF-1), the insulin receptor substrate CHICO, PI3K Dp110 / p60, and PI3K-target PKB. Flies with a mutation in these genes have been reported to significantly increase life expectancy (12, 13).
Surprisingly, the same molecular mechanisms in different tissues do not have the same effect on aging. Several studies of nematodes and fruit flies have shown that a decrease in insulin / IGF-like signaling in nervous and adipose tissue plays a major role in regulating longevity (14, 15). Although it has been shown in invertebrate models that this cascade is important for modulating life expectancy, the effect of insulin / IGF-like signal transmission on life expectancy is much more complex in vertebrates, because they have functionally specific insulin and IGF molecules, IGF binding proteins (IGFBPs ), proteases of IGFBP, GH, multiple receptors and several mechanisms of intracellular signal transduction with different tissue-specific expression (16).
Vertebrate models
Several mutant GH / IGF-1 mice were developed with different targets. The most current models are described below.
Mice Snell and Ames.
Snell and Ames mice are two mouse strains with mutations in the PIT-1 and PROP-1 genes, respectively (17, 18). Since both PIT-1 and PROP-1 proteins are necessary for the differentiation of pituitary cells that produce GH, prolactin and thyroid-stimulating hormone, both types of homozygous mutant mice lack all three hormones (18). These models showed a significant increase in life expectancy (42–70% more than in wild-type mice), increased insulin sensitivity and lower incidence of tumors (19, 20). When Ames mice were subjected to calorie restriction, their lifespan increased even more (21). Although these animals lack three hormones, it has been demonstrated that the increase in life expectancy depends mainly on GH deficiency (22).
Lit / lit mouse
In Lit / lit mice, GH deficiency and mutation in the gene that encodes a GH receptor for hormone (GHRHR). These animals were dwarfs, had increased adipose tissue, a lower incidence of tumors and a longer life expectancy increased by 23–25% (19).
GH-Releasing Hormone-Knockout (GHRH-KO) mouse.
GH-releasing hormone (GHRH-KO) knockout mice live 43% (in females) and 51% (in males) longer than wild-type animals, and have many phenotypic characteristics of Ames mice, such as hypersensitivity to insulin, reduced plasma triglycerides and cholesterol levels, increased adipose tissue, elevated plasma levels of leptin and adiponectin (23).
GH-Receptor-Knockout Mouse (GHR-KO)
GH receptor knockout mice (GHR-KO) have elevated serum GH levels and very low levels of IGF-1. It was also reported that this strain of mice lived 38–55% longer than the wild type (24), and showed a decrease in oxidative stress, as well as a lower and delayed onset of fatal tumors (25). Similar results were observed in df / KO mice, crossed two lines of mice, GHR-KO and Ames dwarfs, who lacked GH and GH receptor and maintained an increase in lifespan (26). Unlike wild siblings and Ames dwarf mice, caloric restriction did not increase the lifespan of GHR-KO mice, suggesting that the GH / IGF-1 axis and calorie restriction may have similar or partially overlapping mechanisms for extending life expectancy (27) .
GH Receptor Antagonism (GHA)
Not all animal models with suppression of the GH / IGF-1 system demonstrate an increase in longevity. The strain GHA mice is one such example. GHA, generated by replacing a single amino acid, is capable of binding the GH receptor with the same affinity as GH, but does not induce intracellular signaling. The life span of GHA mice did not increase significantly (28).
IGF-1R +/– Mice
While most mice with an inactive IGF-1 receptor (IGF-1R - / -) die at birth, animals heterozygous for the mutant IGF-1 receptor allele (IGF-1R ±) showed a very low level of serum IGF-1 , approximately 10% smaller size and 33% longer life expectancy for females and 16% for males. However, in this study, wild-type controls survived to 19 months, which compromised the interpretation of the results (29). Later studies evaluating life expectancy in another IGF-1R ± line showed a slight increase in life expectancy by 5–10%, but only in females (30, 31). In addition, the main background strain appears to affect the extent of life extension in several mouse models (32).
A Brain-Specific IGF1-R +/−
A Brain-Specific IGF1-R +/– mutant mice lived 9% longer than the wild type, which underlines the appropriate role of the nervous system in modulating longevity (33).
Liver-specific IGF-1-disrupted mice (LI-IGF-1 - / -).
Mice with impaired IGF-1 production (LI-IGF-1 - / -) have very low serum levels of IGF-1 and high serum levels of GH due to inactivation of the IGF-1 gene. In LI-IGF-1 - / - mice, reduced obesity was noticeable and, as a result, the weight was 25% lower than in wild-type mice. Only female LI-IGF-1 - /-mice demonstrated an increase in life expectancy of 16% compared with control mice (34).
Pappa - / - mouse.
Pappa - / - mice have a knockout of a pregnancy-associated plasma protein-A gene (Pregnancy-associated plasma protein A, PAPP-A, PAPPA), a specific protease for IGF binding proteins. The average lifespan of this mouse strain was 38% longer compared to wild type controls. Pappa - / - mice were dwarfs, but their serum glucose, insulin, IGF-1, and GH levels did not differ from those of the wild-type controls, suggesting that PAPPA acts mainly at the autocrine or paracrine level. In addition to the increased lifespan in Pappa - / - mice, there was a lower incidence of tumor development, as well as age-related degenerative lesions (35, 36).
IRS Disrupted Mouse (IRS1 - / -).
IRS-1 and -2 are important mediators for insulin, as well as for IGF-1 signaling. IRS1 - / - mice were insulin-resistant, with a defect in insulin signaling mainly in muscle tissue, about 30% smaller in size than the wild type, and only in females the life expectancy was 18% longer than in wild-type animals (37 ). ).
IRS2 - / - mice were also insulin-resistant, but unlike IRS1 - / - mice, they found defects in insulin signaling in more tissues, including liver, adipose tissue, and skeletal muscle. These mice developed diabetes, and their life expectancy was much shorter than that of wild-type mice and IRS2 ± mice. IRS2 +/– mice had improved insulin sensitivity and increased lifespan (+ 18%) compared with wild-type mice. In addition, it was reported that the brain-specific mice IRS2 ± and IRS2 - / - were insulin-resistant and lived 18 and 14% longer than wild-type controls, respectively (38).
KLOTHO Modified Mice.
The KLOTHO protein inhibits insulin and IGF-1 signaling, possibly by disrupting the receptor / ligand interaction. It was reported that KLOTHO over-expression mice had a normal size, and males developed insulin resistance, and the lifespan of both males and females was significantly increased (+18 and + 30%, respectively) (39, 40).
P66shc Disrupted Mouse (P66shc - / -).
P66shc is a protein that mediates IGF-1 signaling downstream of the receptor by activating the MAPK pathway. P66shc - / - mice had a normal phenotype, but lived 28% longer than wild-type controls (41). However, these data were not confirmed in a recent study (42).
The role of GH / IGF-1 / insulin signaling in aging and longevity has been deeply studied in all these animal models. While in invertebrates, the effect of inhibition on IGF-1 / insulin on the lifespan was obvious and significant, in mouse models this effect was weakened and not reproducible in some cases, such as in the IGF-1R ± and P66shc - / - lines mice. However, most of these models showed some common features among long-lived mice, such as reduced levels of circulating IGF-1 and insulin and increased insulin sensitivity, which are likely to reduce the incidence of cancer, improve resistance to stress and prolong life . Genetic changes that can disrupt the IGF-1 system can keep animals healthy for longer periods and can delay or alleviate some age-related diseases. In this process, nervous and fatty tissues play an important role.
In addition, additional data is needed to determine the best point in time during the lifetime to interfere with the suppression of the IGF-1 system in order to obtain a positive effect on longevity. In igf f / f C57B l / 6 mice, the deficit of circulating IGF-1, starting from 5 months or earlier, increased life expectancy by 15% only in females with a decrease in the number of organs with pathology at the end of life compared to the control group . In addition, IGF-1 deficiency at a later age (15 months) reduced the risk of developing cancer, but did not have a positive effect on life expectancy (43). These data highlight the importance of IGF-1 deficiency at an early age to increase longevity. On the other hand, Mao et al. (44) recently reported that the later administration of 18-month-old CB6F1 mice with a monoclonal antibody directed against the IGF-1 receptor extended the life expectancy of females by 9% and improved certain aspects of health.
Centenarian long-livers are considered the best human model for studying the biological determinants of longevity that have reached the most extreme values of human longevity (45).
In several studies, circulating insulin and IGF-1 levels were compared in centenarians with those in younger controls (46).
Metabolic age-related remodeling is a physiological process that occurs throughout the population. Aging is often associated with a decrease in glucose tolerance, which is associated with increased insulin resistance (47), but long-lived people have an exception. It was found (48) that insulin resistance increases with age and decreases in people over 90 years old living in southern Italy. Indeed, long-lived subjects showed higher insulin sensitivity and better beta cell function than younger subjects. This difference also did not depend on the main anthropometric and metabolic factors. In 100-year-old patients, plasma glucose concentration for 2 hours was lower than in elderly patients (mean age 78 years). Long-lived insulin-mediated glucose consumption was higher than that of older controls during euglycemic glucose uptake, which maintained the preserved glucose tolerance and insulin action in this long-lived group (49, 50). Similar results confirming better insulin sensitivity were observed in other populations of long-livers (51, 52).
In addition, long-livers showed a preserved effect of insulin not only on glucose metabolism, but also on adipose tissue. In fact, insulin infusion is usually associated with inhibition of lipolysis and, thus, with a significant decrease in the concentration of free fatty acids and triglycerides in the plasma. In centenarians, the inhibitory activity of insulin in lipolysis was higher than in control participants (mean age 78 years) (50). It should be noted that long-livers have lower sympathetic tone as compared to adult controls, which may be associated with better insulin action and, therefore, low plasma fasting insulin (53, 54).
The life expectancy of the IGF-1 system is still controversial for long-lived subjects (46). Paolisso et al. (55) described an increased ratio of IGF-1 / IGFBP-3 in plasma in healthy centenarians compared with older people. They suggested that this increased ratio indicates a higher bioavailability of IGF-1, which helps to improve the action of insulin in long-livers. Bonafè et al. (56) reported that subjects with at least the A allele of the IGF-1 receptor gene (G / A, codon 1013) had low levels of free IGF-1 in plasma and were more represented among long-lived people. Arai et al. (57) described relatively low levels of serum IGF-1 in the Japanese long-livers population. In this population, the lowest rates of both IGF-1 and IGFBP-3 were associated with increased mortality (58).
These conflicting results likely reflect the complexity of the IGF system and ethnic differences in the registered population. In addition, centenarians were often compared with a control group of younger subjects. Thus, in most of these studies, it was impossible to conclude whether the differences between IGF-1 in both groups were associated with different lifespans or reflected a physiologically dependent reduction in IGF-1. Indeed, there are several limitations to the study of long-livers: (1) low prevalence (1 century old for 5-10 000 inhabitants), (2) presence of weakness due to extreme age (almost 95% of long-livers have at least 1 asthenia criterion), (3 a) lack of a control group of the same age (45, 59). Because of these limitations, this human model is not suitable for studying age variables that may be involved in modulating life expectancy.
The descendants of centenarians are another interesting model for determining the relevant factors associated with human longevity and healthy aging. A consistent set of observations in different countries suggests that the descendants of long-livers are healthier than members of the same demographic groups (51, 60, 61) and biologically (epigenetically) younger than their chronological age (62). In general, these studies show that relatives of long-livers are more likely to live longer and have good health (60, 63). In addition, the study of the offspring of long-livers has the advantage of having a corresponding demographically selected control group consisting of offspring of comparable age, in which both parents were born in the same cohort of centenarians, but died before the threshold age, after which people are classified as “long-livers” . This strategy is crucial to prevent cohort effects. Thus, the model of progeny of long-livers can overcome some of the limitations that are found in the study of long-livers (rarity, weakness and lack of proper control) (60).
In several studies, the IGF-1 / insulin system was characterized in the descendants of long-livers and in the corresponding control group.
We evaluated the circulating bioactivity of IGF-1, measured using an innovative analysis of kinase receptor activation (KIRA), carried out on long-livers, descendants of long-livers and comparable control offspring. The descendants of long-livers and long-livers had a relatively lower circulating biological activity of IGF-1 compared with the control group. Interestingly, the biological activity of IGF-1 in the descendants of long-livers was inversely related to insulin sensitivity (51).
Suh et al. (64) assessed serum IGF-1 levels in descendants of Jewish Ashkenazi long-livers and age-matched controls. In children of long-lived women, the level of IGF-1 in serum was 35% higher than in control participants. This difference may represent a compensatory response to reduced signaling of the IGF-1 receptor. In addition, the Jewish long-livers of Ashkenazy described the excessive presence of heterozygous mutations in the IGF-1 receptor gene, together with relatively high serum IGF-1 levels and weakened IGF-1 receptor activity compared to the control group without family longevity.
To study longevity, other authors examined ninety-year-old brothers and sisters and their descendants. In the Leiden longevity study, 421 families were selected, consisting of at least two reports from lei, brothers and sisters, their descendants and partners of descendants as control. Serum glucose, insulin and triglyceride levels were the best biomarker of healthy aging in these populations (low glucose and insulin levels were considered healthy) (65). Nine-year long-livers in the lowest IGF-1 / IGFBP-3 ratio in the bloodstream were associated with better survival (66). Descendants of nine-year long-livers showed better insulin sensitivity compared with their partners, while similar fasting serum IGF-1 and IGFBP-3 levels were observed in both groups (67). Interesting,that the 24-hour total GH secretion was 28% lower in the offspring compared to control (68).
Another approach taken to study longevity in humans is to select the family components of exceptional longevity and healthy aging, based on strict criteria, such as the indicator on family life expectancy, adopted in the Long Life Family Study. These families, selected for exceptional life expectancy, were compared with a control group without a family history of longevity (69). In this population, circulating levels of IGF-1 turned out to be a reliable age-specific biomarker (70).
In confirmation of the potential role of the GH / IGF-1 / insulin system in human longevity, there are many genetic studies. Indeed, several genetic loci have been found to be associated with circulating levels of IGF-1 and IGFBP-3 and have the potential to affect aging (71). A genome-wide analysis of associations conducted in ninety-year-olds and a population of patients <60 years of age showed a clear relationship between the genetic variability of genes involved in insulin / IGF-1 and the duration of a person’s life (72). In a prospective study of older people, women with a genetic profile indicating a decrease in insulin / IGF-1 signaling activity showed a longer lifespan (73).Four independent cohorts of long-lived people recently described a linear increase in the prevalence of homozygosity for exon 3 (G3R) of the GH receptor with age. The presence of the d3 / d3 genotype increased the lifespan by about 10 years (74).
One of the most convincing observations in the biology of aging is the ability of caloric restriction to prevent or delay some age-related diseases and to increase the lifespan of mammals (75-78). The biological mechanisms of this phenomenon are not entirely clear, but it was suggested that the potential involvement of the corresponding changes in energy metabolism, endocrine system and oxidative damage.
Caloric restriction causes numerous hormonal changes. In rodents, caloric restriction without starvation suppressed circulating levels of IGF-1 and insulin in proportion to the level of restriction, increased insulin sensitivity and resistance to stress and toxicity, and reduced the risk of cancer (79, 80). Interestingly, most of these characteristics observed in wild-type mice during caloric restriction resemble those reported in mice that are long-lived due to a genetic disorder in GH / IGF-1 / insulin signaling, as previously described.
Randomized human clinical trials have shown that caloric restriction does not reduce serum IGF-1 levels if protein intake does not decrease (81, 82). However, a recent meta-analysis that assessed the effects of food restriction on generally accepted biomarkers of healthy aging showed a decrease in human IGF-1 levels (83).
Other hormonal changes, such as decreased insulin levels, thyroid hormones and leptin levels, as well as increased adiponectin levels and insulin sensitivity, were observed during diet restriction (85, 86).
This hormonal adaptation can play an important role in prolonging life through several mechanisms:
1) Reduced metabolic rate, cell proliferation and oxidative stress. In fact, IGF-1 is a powerful growth factor, and thyroid hormone is a powerful stimulator of basal metabolic rate and oxidative metabolism. In addition, transcription patterns suggest that chronic moderate calorie restriction in adults slows down the aging process, switching cell metabolism from growth to maintenance and restoration of activity (84).
2) Reducing the accumulation of senescent cells. Cell aging has been shown to be a key mediator of aging (87). Over time, protein homeostasis decreases and damage accumulates. Interestingly, some age-related diseases can be delayed by weakening the accumulation of senescent cells (88, 89). Typically, the mTOR pathway is activated by several signals, including nutrients, IGF-1 and insulin (Fig. 2).). The decline in regulation of this path, which was reported after calorie restriction, increased the life span of some organisms. This effect seems to be secondary to the enhancement of autophagy, a cytoprotective process of digestion. In fact, autophagy is a process of processing cells that can remove old or damaged cellular components, preventing the accumulation of aging cells (90,91).
3) Anti-inflammation. Dietary intervention in both animals and humans can slow down the aging process, weakening the mild inflammatory status (83, 92). The mechanisms underlying the anti-inflammatory activity of food restriction are not clearly defined. This effect is believed to be due to a decrease in fat mass and pro-inflammatory adipokines, as well as an improvement in the integrity of the intestinal barrier observed during dietary intervention (93, 94).
It is interesting to note that the endocrine biochemical profile observed in subjects during caloric restriction is comparable to that of long-livers, which confirms the potential role of the endocrine system in modulating longevity. In addition to increasing insulin sensitivity and lowering plasma / serum IGF-1 levels, several studies have shown increased levels of circulating adiponectin and reduced levels of circulating leptin and thyroid hormones in long-lived people compared with younger subjects.
Adipose tissue is an endocrine organ that produces several cytokines that are involved in relevant processes, such as energy metabolism, lipid and glucose homeostasis, and modulation of the inflammatory response. Visceral adipose tissue plays a major role in the development of metabolic diseases (95). Aging is associated with an increase in fat mass and redistribution of adipose tissue, characterized by loss of peripheral subcutaneous fat and accumulation of visceral fat. In the elderly, changes in the secretion, synthesis, and function of adipokines have been described, probably due to an imbalance in function, proliferation, size and number of fat cells (86). Adiponectin is an insulin-sensitizing, anti-inflammatory and anti-atherogenic cytokine. Adiponectin circulates in the blood in several forms: trimer, hexamer,high molecular weight multimer (HMW) and globular adiponectin (proteolytically cleaved form). The HMW multimer is believed to be the more active form of adiponectin while protecting against insulin resistance and diabetes (96). Circulating adiponectin is independently and negatively associated with aspects of the metabolic syndrome, including insulin resistance, body weight, blood pressure, and serum lipids. Leptin is mainly produced in the subcutaneous and to a lesser extent in visceral white adipose tissue. This cytokine regulates food intake, energy expenditure and atherogenesis. Leptin contributes to weight loss by reducing appetite and stimulating metabolism and has pro-inflammatory properties (97).that HMW multimer is a more active form of adiponectin, while protecting against insulin resistance and diabetes (96). Circulating adiponectin is independently and negatively associated with aspects of the metabolic syndrome, including insulin resistance, body weight, blood pressure, and serum lipids. Leptin is mainly produced in the subcutaneous and to a lesser extent in visceral white adipose tissue. This cytokine regulates food intake, energy expenditure and atherogenesis. Leptin contributes to weight loss by reducing appetite and stimulating metabolism and has pro-inflammatory properties (97).that HMW multimer is a more active form of adiponectin, while protecting against insulin resistance and diabetes (96). Circulating adiponectin is independently and negatively associated with aspects of the metabolic syndrome, including insulin resistance, body weight, blood pressure, and serum lipids. Leptin is mainly produced in the subcutaneous and to a lesser extent in visceral white adipose tissue. This cytokine regulates food intake, energy expenditure and atherogenesis. Leptin contributes to weight loss by reducing appetite and stimulating metabolism and has pro-inflammatory properties (97).blood pressure and serum lipids. Leptin is mainly produced in the subcutaneous and to a lesser extent in visceral white adipose tissue. This cytokine regulates food intake, energy expenditure and atherogenesis. Leptin contributes to weight loss by reducing appetite and stimulating metabolism and has pro-inflammatory properties (97).blood pressure and serum lipids. Leptin is mainly produced in the subcutaneous and to a lesser extent in visceral white adipose tissue. This cytokine regulates food intake, energy expenditure and atherogenesis. Leptin contributes to weight loss by reducing appetite and stimulating metabolism and has pro-inflammatory properties (97).
Several studies have reported that long-livers have a higher plasma level of adiponectin and lower concentrations of leptin than younger controls (53, 98 - 102). All forms of adiponectin were significantly increased in long-livers, but the HMW multimer was significantly higher (99). In long-livers, high adiponectin concentrations were independent of BMI, renal or cardiovascular function, and were associated with a favorable metabolic phenotype (higher cholesterol-HDL cholesterol level, lower glycated hemoglobin, insulin, HOMA-IR, and triglycerides) (98, 99). Elevated levels of adiponectin have also been found in the descendants of long-lived subjects (over 95 years old) (103).
A decrease in the level of thyroid hormones seems to be characteristic of long-livers. Mariotti et al. (104) reported that healthy long-livers had lower serum TSH and FT3 levels and higher serum rT3 levels than those observed in other control groups. In the other Italian population of long-livers, the total T4 values were below the normal range in 60% of the surveyed (105). Baranovskaya et al. reported that serum T3 levels in long-livers were lower compared with those in early elderly and young women (52). Recently, we characterized the thyroid function profile in an Italian cohort of 672 patients (aged 52–113 years). The age-related decline in the FT3 level and the FT3 / FT4 ratios are noted, while FT4 and TSH increase with age (106).In Chinese long-lived families, a decrease in thyroid function (high TSH and low FT3 concentration) seems to be related to age, and this phenotype is hereditary (107).
Corsonello et al. (108) found in relatives of long-livers (offspring or nieces / nephews) lower comorbidities, FT3, FT4 and TSH levels, than in age-matched controls that were not relatives of long-livers. In another Italian population, a lower plasma level of FT4 was observed in the descendants of long-livers compared with the control group of the same age (60).
In general, long-livers are thin (109) and adhere to healthy eating habits (110). Like subjects during caloric restriction, centenarians experienced slower cell growth / metabolism, better control of signal transduction and increased autophagy. Through the analysis of DNA methylation throughout the genome of long-livers and their descendants, we identified epigenetically modulated genes and pathways that are potentially involved in the process of aging and longevity. Our results suggest that these populations were characterized by better preservation of DNA methylation status, slower cell growth / metabolism, and better control of signal transmission through epigenetic mechanisms (111). The longevity of the bioenergetic function due to mitochondrial hypertrophy,which can compensate for functional defects (112). In addition, healthy longevity has high levels of autophagy, as evidenced by higher levels of baclin-1 in serum compared with young patients with myocardial infarction and with healthy controls (113). An increase in autophagic activity was also observed in subjects belonging to families with exceptional longevity (114).
The corresponding phenomenon arises in relation to the inflammatory status, which is weakened in subjects after caloric restriction (115, 116) and high in long-livers (117-119). With aging, a state of mild and chronic inflammatory pathology (age inflammation) and an increased prevalence of a number of diseases, such as cardiovascular diseases, atherosclerosis, tumors, cognitive impairment, osteoarthritis and diabetes (120, 121), are observed. Consequently, the weakening of the chronic inflammatory status after caloric restriction is a beneficial effect. Centenarian long-livers show signs of inflammation, but at the same time seem to be spared from its harmful effects. This obvious paradox can be explained by the factthat long-livers have a complex and peculiar balance between pro-inflammatory and anti-inflammatory factors, which leads to a slower, more limited and balanced development of inflammation compared with the elderly, which are characterized by an ineffective response to counteracting chronic inflammation (120, 121).
These data suggest the general mechanisms for increasing life expectancy and postponing age-related diseases that are found in centenarians and mammals during a calorie restricted diet.
Opinion of the authors.
Preclinical models provided a deep insight into the aging process using consistent data that takes into account the role of the GH / IGF-1 / insulin system in modulating life expectancy. Although it is well known that insulin sensitivity and low insulin levels are associated with improved survival, there is some evidence that weakening the GH / IGF-1 axis can have a beneficial effect on increasing longevity in humans. However, it is still unknown what the optimal levels of IGF-1 are for life, to live longer and be healthier. In addition, the sensitivity of the IGF-1 receptor and the activation of the post-receptor pathway were not evaluated in most studies involving long-lived subjects. Consequently,It is not possible to determine the actual activation status of IGF-1 receptor signaling through a simple dose of circulating levels of IGF-1. This makes it difficult to determine pharmacological or environmental strategies aimed at this system to increase longevity and promote healthy aging. A comprehensive understanding of these aspects remains the main problem for identifying interventions aimed at slowing the aging of a person, and application in rehabilitation medicine. Future studies should assess the functional status of IGF-1 receptor signaling, including through transcription profiling and analysis of functional networks related to IGF-1 regulated genes, in long-lived subjects.This makes it difficult to determine pharmacological or environmental strategies aimed at this system to increase longevity and promote healthy aging. A comprehensive understanding of these aspects remains the main problem for identifying interventions aimed at slowing the aging of a person, and application in rehabilitation medicine. Future studies should assess the functional status of IGF-1 receptor signaling, including through transcription profiling and analysis of functional networks related to IGF-1 regulated genes, in long-lived subjects.This makes it difficult to determine pharmacological or environmental strategies aimed at this system to increase longevity and promote healthy aging. A comprehensive understanding of these aspects remains the main problem for identifying interventions aimed at slowing the aging of a person, and application in rehabilitation medicine. Future studies should assess the functional status of IGF-1 receptor signaling, including through transcription profiling and analysis of functional networks related to IGF-1 regulated genes, in long-lived subjects.and applications in rehabilitation medicine. Future studies should assess the functional status of IGF-1 receptor signaling, including through transcription profiling and analysis of functional networks related to IGF-1 regulated genes, in long-lived subjects.and applications in rehabilitation medicine. Future studies should assess the functional status of IGF-1 receptor signaling, including through transcription profiling and analysis of functional networks related to IGF-1 regulated genes, in long-lived subjects.
findings
A striking similarity has been described with respect to the endocrine profile between the long-livers and the subjects after a calorie restricted diet. The endocrine and metabolic adaptations observed in both models may represent a physiological strategy for increasing longevity due to slower cell growth / metabolism, slower loss of natural physiological reserve, transition of cell metabolism from cell proliferation to regenerative activity and reduction of the accumulation of aging cells. These mechanisms appear to be, at least in part, mediated by modulation of the GH / IGF-1 / insulin system.
Introduction.
Aging is defined as the physiological decline of biological functions in the body with a progressive decrease or loss of adaptation to internal and external damage. In humans, the aging phenotype is extremely heterogeneous and can be described as a complex mosaic resulting from the interaction of several random and environmental events, genetic and epigenetic changes accumulated over a lifetime. Despite its enormous complexity, the molecular basis of aging is limited to the few highly evolutionarily conservative biological mechanisms responsible for maintaining and restoring the body (1).
In the past 3 decades, one of the most discussed topics in gerontology is the role of the growth hormone (GH) / insulin-like growth factor-1 (IGF-1) / insulin system in the regulation of longevity. Accumulated evidence suggests that this pathway plays an important role in the pathogenesis of a number of age-related diseases, including cancer, dementia, cardiovascular and metabolic diseases (2–4).
')
In animal models, it has been shown that the suppression of the GH / IGF-1 / insulin system significantly increases life expectancy. However, data is contradictory in humans (5, 6).
This review describes recent advances in the study of the IGF-1 system and modulation of longevity, hypothesizing that the endocrine and metabolic adaptations observed in centenarians and mammals during calorie restriction may be a physiological strategy for increasing longevity due to slower cell growth / metabolism, better control of signal transduction and physiological reserve power and reduced accumulation of aging cells.
IGF-1 system and durability in animal models
Figure 1 Pleiotropic effect of IGF-1 on the body. On one side of the scale, which outweighs: tissue homeostasis, cardioprotective and neuroprotective effects, insulin-like effects, participation in the formation of the skeleton and muscle regeneration. On the second scale: the risk of carcinogenesis.
The IGF-1 system has several pleiotropic effects on biological aging (see figure 1). IGF-1 plays an important role in fetal development, growth in childhood and adolescence, and adult tissue homeostasis. In addition, IGF-1, apparently, has atheroprotective action, neural protective and insulin-like action (in high concentrations), regulates bone metabolism and muscle regeneration. However, IGF-1 is a major risk factor in the development of several types of tumors due to its strong proliferative activity, mainly due to modulation of the cell cycle, apoptosis and cell survival (7-9). Most of these effects are mediated by interaction with the insulin receptor substrate (IRS) -1 and-2 and modulation of the mammalian PI3K / AKT pathway / target of rapamycin in mammals (mTOR) (see Figure 2)
Fig.2 Schematic representation of several components of the IGF-1 / PI3K / AKT / mTOR path, discussed in this review. IGF-1 increases AKT activity with corresponding effects on cell survival and proliferation, glucose metabolism and protein synthesis.
Several preclinical studies have reported that mutations in the genes controlling the GH / IGF-1 / insulin signaling pathway can significantly increase life expectancy in both invertebrate and vertebrate animal models (5, 6).
Invertebrate models.
In the invertebrate, the insulin / IGF-like cascade is regulated by several peptides capable of interacting with one common insulin / IGF-1-like receptor.
In the nematode Caenorhabditis elegans, insulin / IGF-like pathway consists of several proteins encoded by the genes daf-2, age-1 (encoding the catalytic subunit PI3K), akt-1, akt-2, pdk-1, sgk-1 (serine-threonine kinase ), daf-16, skn-1 and daf-18 (PTEN, phosphatase, involved in the inhibition of the AKT signaling pathway). The reduced activity of the daf-2, age-1, akt-1, akt-2, pdk-1, sgk-1 genes suppressed this path, and animals with these mutations have been reported to age more slowly and have an increased lifespan. up to 300%. In contrast, stimulation of the insulin / IGF-like pathway reduces the lifespan of nematodes (10, 11).
In the Drosophila melanogaster fruit fly, insulin-like / IGF-like signaling consists of dINR (a protein similar to insulin receptor / IGF-1), the insulin receptor substrate CHICO, PI3K Dp110 / p60, and PI3K-target PKB. Flies with a mutation in these genes have been reported to significantly increase life expectancy (12, 13).
Surprisingly, the same molecular mechanisms in different tissues do not have the same effect on aging. Several studies of nematodes and fruit flies have shown that a decrease in insulin / IGF-like signaling in nervous and adipose tissue plays a major role in regulating longevity (14, 15). Although it has been shown in invertebrate models that this cascade is important for modulating life expectancy, the effect of insulin / IGF-like signal transmission on life expectancy is much more complex in vertebrates, because they have functionally specific insulin and IGF molecules, IGF binding proteins (IGFBPs ), proteases of IGFBP, GH, multiple receptors and several mechanisms of intracellular signal transduction with different tissue-specific expression (16).
Vertebrate models
Several mutant GH / IGF-1 mice were developed with different targets. The most current models are described below.
Mice Snell and Ames.
Snell and Ames mice are two mouse strains with mutations in the PIT-1 and PROP-1 genes, respectively (17, 18). Since both PIT-1 and PROP-1 proteins are necessary for the differentiation of pituitary cells that produce GH, prolactin and thyroid-stimulating hormone, both types of homozygous mutant mice lack all three hormones (18). These models showed a significant increase in life expectancy (42–70% more than in wild-type mice), increased insulin sensitivity and lower incidence of tumors (19, 20). When Ames mice were subjected to calorie restriction, their lifespan increased even more (21). Although these animals lack three hormones, it has been demonstrated that the increase in life expectancy depends mainly on GH deficiency (22).
Lit / lit mouse
In Lit / lit mice, GH deficiency and mutation in the gene that encodes a GH receptor for hormone (GHRHR). These animals were dwarfs, had increased adipose tissue, a lower incidence of tumors and a longer life expectancy increased by 23–25% (19).
GH-Releasing Hormone-Knockout (GHRH-KO) mouse.
GH-releasing hormone (GHRH-KO) knockout mice live 43% (in females) and 51% (in males) longer than wild-type animals, and have many phenotypic characteristics of Ames mice, such as hypersensitivity to insulin, reduced plasma triglycerides and cholesterol levels, increased adipose tissue, elevated plasma levels of leptin and adiponectin (23).
GH-Receptor-Knockout Mouse (GHR-KO)
GH receptor knockout mice (GHR-KO) have elevated serum GH levels and very low levels of IGF-1. It was also reported that this strain of mice lived 38–55% longer than the wild type (24), and showed a decrease in oxidative stress, as well as a lower and delayed onset of fatal tumors (25). Similar results were observed in df / KO mice, crossed two lines of mice, GHR-KO and Ames dwarfs, who lacked GH and GH receptor and maintained an increase in lifespan (26). Unlike wild siblings and Ames dwarf mice, caloric restriction did not increase the lifespan of GHR-KO mice, suggesting that the GH / IGF-1 axis and calorie restriction may have similar or partially overlapping mechanisms for extending life expectancy (27) .
GH Receptor Antagonism (GHA)
Not all animal models with suppression of the GH / IGF-1 system demonstrate an increase in longevity. The strain GHA mice is one such example. GHA, generated by replacing a single amino acid, is capable of binding the GH receptor with the same affinity as GH, but does not induce intracellular signaling. The life span of GHA mice did not increase significantly (28).
IGF-1R +/– Mice
While most mice with an inactive IGF-1 receptor (IGF-1R - / -) die at birth, animals heterozygous for the mutant IGF-1 receptor allele (IGF-1R ±) showed a very low level of serum IGF-1 , approximately 10% smaller size and 33% longer life expectancy for females and 16% for males. However, in this study, wild-type controls survived to 19 months, which compromised the interpretation of the results (29). Later studies evaluating life expectancy in another IGF-1R ± line showed a slight increase in life expectancy by 5–10%, but only in females (30, 31). In addition, the main background strain appears to affect the extent of life extension in several mouse models (32).
A Brain-Specific IGF1-R +/−
A Brain-Specific IGF1-R +/– mutant mice lived 9% longer than the wild type, which underlines the appropriate role of the nervous system in modulating longevity (33).
Liver-specific IGF-1-disrupted mice (LI-IGF-1 - / -).
Mice with impaired IGF-1 production (LI-IGF-1 - / -) have very low serum levels of IGF-1 and high serum levels of GH due to inactivation of the IGF-1 gene. In LI-IGF-1 - / - mice, reduced obesity was noticeable and, as a result, the weight was 25% lower than in wild-type mice. Only female LI-IGF-1 - /-mice demonstrated an increase in life expectancy of 16% compared with control mice (34).
Pappa - / - mouse.
Pappa - / - mice have a knockout of a pregnancy-associated plasma protein-A gene (Pregnancy-associated plasma protein A, PAPP-A, PAPPA), a specific protease for IGF binding proteins. The average lifespan of this mouse strain was 38% longer compared to wild type controls. Pappa - / - mice were dwarfs, but their serum glucose, insulin, IGF-1, and GH levels did not differ from those of the wild-type controls, suggesting that PAPPA acts mainly at the autocrine or paracrine level. In addition to the increased lifespan in Pappa - / - mice, there was a lower incidence of tumor development, as well as age-related degenerative lesions (35, 36).
IRS Disrupted Mouse (IRS1 - / -).
IRS-1 and -2 are important mediators for insulin, as well as for IGF-1 signaling. IRS1 - / - mice were insulin-resistant, with a defect in insulin signaling mainly in muscle tissue, about 30% smaller in size than the wild type, and only in females the life expectancy was 18% longer than in wild-type animals (37 ). ).
IRS2 - / - mice were also insulin-resistant, but unlike IRS1 - / - mice, they found defects in insulin signaling in more tissues, including liver, adipose tissue, and skeletal muscle. These mice developed diabetes, and their life expectancy was much shorter than that of wild-type mice and IRS2 ± mice. IRS2 +/– mice had improved insulin sensitivity and increased lifespan (+ 18%) compared with wild-type mice. In addition, it was reported that the brain-specific mice IRS2 ± and IRS2 - / - were insulin-resistant and lived 18 and 14% longer than wild-type controls, respectively (38).
KLOTHO Modified Mice.
The KLOTHO protein inhibits insulin and IGF-1 signaling, possibly by disrupting the receptor / ligand interaction. It was reported that KLOTHO over-expression mice had a normal size, and males developed insulin resistance, and the lifespan of both males and females was significantly increased (+18 and + 30%, respectively) (39, 40).
P66shc Disrupted Mouse (P66shc - / -).
P66shc is a protein that mediates IGF-1 signaling downstream of the receptor by activating the MAPK pathway. P66shc - / - mice had a normal phenotype, but lived 28% longer than wild-type controls (41). However, these data were not confirmed in a recent study (42).
The role of GH / IGF-1 / insulin signaling in aging and longevity has been deeply studied in all these animal models. While in invertebrates, the effect of inhibition on IGF-1 / insulin on the lifespan was obvious and significant, in mouse models this effect was weakened and not reproducible in some cases, such as in the IGF-1R ± and P66shc - / - lines mice. However, most of these models showed some common features among long-lived mice, such as reduced levels of circulating IGF-1 and insulin and increased insulin sensitivity, which are likely to reduce the incidence of cancer, improve resistance to stress and prolong life . Genetic changes that can disrupt the IGF-1 system can keep animals healthy for longer periods and can delay or alleviate some age-related diseases. In this process, nervous and fatty tissues play an important role.
In addition, additional data is needed to determine the best point in time during the lifetime to interfere with the suppression of the IGF-1 system in order to obtain a positive effect on longevity. In igf f / f C57B l / 6 mice, the deficit of circulating IGF-1, starting from 5 months or earlier, increased life expectancy by 15% only in females with a decrease in the number of organs with pathology at the end of life compared to the control group . In addition, IGF-1 deficiency at a later age (15 months) reduced the risk of developing cancer, but did not have a positive effect on life expectancy (43). These data highlight the importance of IGF-1 deficiency at an early age to increase longevity. On the other hand, Mao et al. (44) recently reported that the later administration of 18-month-old CB6F1 mice with a monoclonal antibody directed against the IGF-1 receptor extended the life expectancy of females by 9% and improved certain aspects of health.
IGF-1 system in long-lived people
Centenarian long-livers are considered the best human model for studying the biological determinants of longevity that have reached the most extreme values of human longevity (45).
In several studies, circulating insulin and IGF-1 levels were compared in centenarians with those in younger controls (46).
Metabolic age-related remodeling is a physiological process that occurs throughout the population. Aging is often associated with a decrease in glucose tolerance, which is associated with increased insulin resistance (47), but long-lived people have an exception. It was found (48) that insulin resistance increases with age and decreases in people over 90 years old living in southern Italy. Indeed, long-lived subjects showed higher insulin sensitivity and better beta cell function than younger subjects. This difference also did not depend on the main anthropometric and metabolic factors. In 100-year-old patients, plasma glucose concentration for 2 hours was lower than in elderly patients (mean age 78 years). Long-lived insulin-mediated glucose consumption was higher than that of older controls during euglycemic glucose uptake, which maintained the preserved glucose tolerance and insulin action in this long-lived group (49, 50). Similar results confirming better insulin sensitivity were observed in other populations of long-livers (51, 52).
In addition, long-livers showed a preserved effect of insulin not only on glucose metabolism, but also on adipose tissue. In fact, insulin infusion is usually associated with inhibition of lipolysis and, thus, with a significant decrease in the concentration of free fatty acids and triglycerides in the plasma. In centenarians, the inhibitory activity of insulin in lipolysis was higher than in control participants (mean age 78 years) (50). It should be noted that long-livers have lower sympathetic tone as compared to adult controls, which may be associated with better insulin action and, therefore, low plasma fasting insulin (53, 54).
The life expectancy of the IGF-1 system is still controversial for long-lived subjects (46). Paolisso et al. (55) described an increased ratio of IGF-1 / IGFBP-3 in plasma in healthy centenarians compared with older people. They suggested that this increased ratio indicates a higher bioavailability of IGF-1, which helps to improve the action of insulin in long-livers. Bonafè et al. (56) reported that subjects with at least the A allele of the IGF-1 receptor gene (G / A, codon 1013) had low levels of free IGF-1 in plasma and were more represented among long-lived people. Arai et al. (57) described relatively low levels of serum IGF-1 in the Japanese long-livers population. In this population, the lowest rates of both IGF-1 and IGFBP-3 were associated with increased mortality (58).
These conflicting results likely reflect the complexity of the IGF system and ethnic differences in the registered population. In addition, centenarians were often compared with a control group of younger subjects. Thus, in most of these studies, it was impossible to conclude whether the differences between IGF-1 in both groups were associated with different lifespans or reflected a physiologically dependent reduction in IGF-1. Indeed, there are several limitations to the study of long-livers: (1) low prevalence (1 century old for 5-10 000 inhabitants), (2) presence of weakness due to extreme age (almost 95% of long-livers have at least 1 asthenia criterion), (3 a) lack of a control group of the same age (45, 59). Because of these limitations, this human model is not suitable for studying age variables that may be involved in modulating life expectancy.
The descendants of centenarians are another interesting model for determining the relevant factors associated with human longevity and healthy aging. A consistent set of observations in different countries suggests that the descendants of long-livers are healthier than members of the same demographic groups (51, 60, 61) and biologically (epigenetically) younger than their chronological age (62). In general, these studies show that relatives of long-livers are more likely to live longer and have good health (60, 63). In addition, the study of the offspring of long-livers has the advantage of having a corresponding demographically selected control group consisting of offspring of comparable age, in which both parents were born in the same cohort of centenarians, but died before the threshold age, after which people are classified as “long-livers” . This strategy is crucial to prevent cohort effects. Thus, the model of progeny of long-livers can overcome some of the limitations that are found in the study of long-livers (rarity, weakness and lack of proper control) (60).
In several studies, the IGF-1 / insulin system was characterized in the descendants of long-livers and in the corresponding control group.
We evaluated the circulating bioactivity of IGF-1, measured using an innovative analysis of kinase receptor activation (KIRA), carried out on long-livers, descendants of long-livers and comparable control offspring. The descendants of long-livers and long-livers had a relatively lower circulating biological activity of IGF-1 compared with the control group. Interestingly, the biological activity of IGF-1 in the descendants of long-livers was inversely related to insulin sensitivity (51).
Suh et al. (64) assessed serum IGF-1 levels in descendants of Jewish Ashkenazi long-livers and age-matched controls. In children of long-lived women, the level of IGF-1 in serum was 35% higher than in control participants. This difference may represent a compensatory response to reduced signaling of the IGF-1 receptor. In addition, the Jewish long-livers of Ashkenazy described the excessive presence of heterozygous mutations in the IGF-1 receptor gene, together with relatively high serum IGF-1 levels and weakened IGF-1 receptor activity compared to the control group without family longevity.
To study longevity, other authors examined ninety-year-old brothers and sisters and their descendants. In the Leiden longevity study, 421 families were selected, consisting of at least two reports from lei, brothers and sisters, their descendants and partners of descendants as control. Serum glucose, insulin and triglyceride levels were the best biomarker of healthy aging in these populations (low glucose and insulin levels were considered healthy) (65). Nine-year long-livers in the lowest IGF-1 / IGFBP-3 ratio in the bloodstream were associated with better survival (66). Descendants of nine-year long-livers showed better insulin sensitivity compared with their partners, while similar fasting serum IGF-1 and IGFBP-3 levels were observed in both groups (67). Interesting,that the 24-hour total GH secretion was 28% lower in the offspring compared to control (68).
Another approach taken to study longevity in humans is to select the family components of exceptional longevity and healthy aging, based on strict criteria, such as the indicator on family life expectancy, adopted in the Long Life Family Study. These families, selected for exceptional life expectancy, were compared with a control group without a family history of longevity (69). In this population, circulating levels of IGF-1 turned out to be a reliable age-specific biomarker (70).
In confirmation of the potential role of the GH / IGF-1 / insulin system in human longevity, there are many genetic studies. Indeed, several genetic loci have been found to be associated with circulating levels of IGF-1 and IGFBP-3 and have the potential to affect aging (71). A genome-wide analysis of associations conducted in ninety-year-olds and a population of patients <60 years of age showed a clear relationship between the genetic variability of genes involved in insulin / IGF-1 and the duration of a person’s life (72). In a prospective study of older people, women with a genetic profile indicating a decrease in insulin / IGF-1 signaling activity showed a longer lifespan (73).Four independent cohorts of long-lived people recently described a linear increase in the prevalence of homozygosity for exon 3 (G3R) of the GH receptor with age. The presence of the d3 / d3 genotype increased the lifespan by about 10 years (74).
IGF-1 system and calorie restriction
One of the most convincing observations in the biology of aging is the ability of caloric restriction to prevent or delay some age-related diseases and to increase the lifespan of mammals (75-78). The biological mechanisms of this phenomenon are not entirely clear, but it was suggested that the potential involvement of the corresponding changes in energy metabolism, endocrine system and oxidative damage.
Caloric restriction causes numerous hormonal changes. In rodents, caloric restriction without starvation suppressed circulating levels of IGF-1 and insulin in proportion to the level of restriction, increased insulin sensitivity and resistance to stress and toxicity, and reduced the risk of cancer (79, 80). Interestingly, most of these characteristics observed in wild-type mice during caloric restriction resemble those reported in mice that are long-lived due to a genetic disorder in GH / IGF-1 / insulin signaling, as previously described.
Randomized human clinical trials have shown that caloric restriction does not reduce serum IGF-1 levels if protein intake does not decrease (81, 82). However, a recent meta-analysis that assessed the effects of food restriction on generally accepted biomarkers of healthy aging showed a decrease in human IGF-1 levels (83).
Other hormonal changes, such as decreased insulin levels, thyroid hormones and leptin levels, as well as increased adiponectin levels and insulin sensitivity, were observed during diet restriction (85, 86).
This hormonal adaptation can play an important role in prolonging life through several mechanisms:
1) Reduced metabolic rate, cell proliferation and oxidative stress. In fact, IGF-1 is a powerful growth factor, and thyroid hormone is a powerful stimulator of basal metabolic rate and oxidative metabolism. In addition, transcription patterns suggest that chronic moderate calorie restriction in adults slows down the aging process, switching cell metabolism from growth to maintenance and restoration of activity (84).
2) Reducing the accumulation of senescent cells. Cell aging has been shown to be a key mediator of aging (87). Over time, protein homeostasis decreases and damage accumulates. Interestingly, some age-related diseases can be delayed by weakening the accumulation of senescent cells (88, 89). Typically, the mTOR pathway is activated by several signals, including nutrients, IGF-1 and insulin (Fig. 2).). The decline in regulation of this path, which was reported after calorie restriction, increased the life span of some organisms. This effect seems to be secondary to the enhancement of autophagy, a cytoprotective process of digestion. In fact, autophagy is a process of processing cells that can remove old or damaged cellular components, preventing the accumulation of aging cells (90,91).
3) Anti-inflammation. Dietary intervention in both animals and humans can slow down the aging process, weakening the mild inflammatory status (83, 92). The mechanisms underlying the anti-inflammatory activity of food restriction are not clearly defined. This effect is believed to be due to a decrease in fat mass and pro-inflammatory adipokines, as well as an improvement in the integrity of the intestinal barrier observed during dietary intervention (93, 94).
It is interesting to note that the endocrine biochemical profile observed in subjects during caloric restriction is comparable to that of long-livers, which confirms the potential role of the endocrine system in modulating longevity. In addition to increasing insulin sensitivity and lowering plasma / serum IGF-1 levels, several studies have shown increased levels of circulating adiponectin and reduced levels of circulating leptin and thyroid hormones in long-lived people compared with younger subjects.
Adipose tissue is an endocrine organ that produces several cytokines that are involved in relevant processes, such as energy metabolism, lipid and glucose homeostasis, and modulation of the inflammatory response. Visceral adipose tissue plays a major role in the development of metabolic diseases (95). Aging is associated with an increase in fat mass and redistribution of adipose tissue, characterized by loss of peripheral subcutaneous fat and accumulation of visceral fat. In the elderly, changes in the secretion, synthesis, and function of adipokines have been described, probably due to an imbalance in function, proliferation, size and number of fat cells (86). Adiponectin is an insulin-sensitizing, anti-inflammatory and anti-atherogenic cytokine. Adiponectin circulates in the blood in several forms: trimer, hexamer,high molecular weight multimer (HMW) and globular adiponectin (proteolytically cleaved form). The HMW multimer is believed to be the more active form of adiponectin while protecting against insulin resistance and diabetes (96). Circulating adiponectin is independently and negatively associated with aspects of the metabolic syndrome, including insulin resistance, body weight, blood pressure, and serum lipids. Leptin is mainly produced in the subcutaneous and to a lesser extent in visceral white adipose tissue. This cytokine regulates food intake, energy expenditure and atherogenesis. Leptin contributes to weight loss by reducing appetite and stimulating metabolism and has pro-inflammatory properties (97).that HMW multimer is a more active form of adiponectin, while protecting against insulin resistance and diabetes (96). Circulating adiponectin is independently and negatively associated with aspects of the metabolic syndrome, including insulin resistance, body weight, blood pressure, and serum lipids. Leptin is mainly produced in the subcutaneous and to a lesser extent in visceral white adipose tissue. This cytokine regulates food intake, energy expenditure and atherogenesis. Leptin contributes to weight loss by reducing appetite and stimulating metabolism and has pro-inflammatory properties (97).that HMW multimer is a more active form of adiponectin, while protecting against insulin resistance and diabetes (96). Circulating adiponectin is independently and negatively associated with aspects of the metabolic syndrome, including insulin resistance, body weight, blood pressure, and serum lipids. Leptin is mainly produced in the subcutaneous and to a lesser extent in visceral white adipose tissue. This cytokine regulates food intake, energy expenditure and atherogenesis. Leptin contributes to weight loss by reducing appetite and stimulating metabolism and has pro-inflammatory properties (97).blood pressure and serum lipids. Leptin is mainly produced in the subcutaneous and to a lesser extent in visceral white adipose tissue. This cytokine regulates food intake, energy expenditure and atherogenesis. Leptin contributes to weight loss by reducing appetite and stimulating metabolism and has pro-inflammatory properties (97).blood pressure and serum lipids. Leptin is mainly produced in the subcutaneous and to a lesser extent in visceral white adipose tissue. This cytokine regulates food intake, energy expenditure and atherogenesis. Leptin contributes to weight loss by reducing appetite and stimulating metabolism and has pro-inflammatory properties (97).
Several studies have reported that long-livers have a higher plasma level of adiponectin and lower concentrations of leptin than younger controls (53, 98 - 102). All forms of adiponectin were significantly increased in long-livers, but the HMW multimer was significantly higher (99). In long-livers, high adiponectin concentrations were independent of BMI, renal or cardiovascular function, and were associated with a favorable metabolic phenotype (higher cholesterol-HDL cholesterol level, lower glycated hemoglobin, insulin, HOMA-IR, and triglycerides) (98, 99). Elevated levels of adiponectin have also been found in the descendants of long-lived subjects (over 95 years old) (103).
A decrease in the level of thyroid hormones seems to be characteristic of long-livers. Mariotti et al. (104) reported that healthy long-livers had lower serum TSH and FT3 levels and higher serum rT3 levels than those observed in other control groups. In the other Italian population of long-livers, the total T4 values were below the normal range in 60% of the surveyed (105). Baranovskaya et al. reported that serum T3 levels in long-livers were lower compared with those in early elderly and young women (52). Recently, we characterized the thyroid function profile in an Italian cohort of 672 patients (aged 52–113 years). The age-related decline in the FT3 level and the FT3 / FT4 ratios are noted, while FT4 and TSH increase with age (106).In Chinese long-lived families, a decrease in thyroid function (high TSH and low FT3 concentration) seems to be related to age, and this phenotype is hereditary (107).
Corsonello et al. (108) found in relatives of long-livers (offspring or nieces / nephews) lower comorbidities, FT3, FT4 and TSH levels, than in age-matched controls that were not relatives of long-livers. In another Italian population, a lower plasma level of FT4 was observed in the descendants of long-livers compared with the control group of the same age (60).
In general, long-livers are thin (109) and adhere to healthy eating habits (110). Like subjects during caloric restriction, centenarians experienced slower cell growth / metabolism, better control of signal transduction and increased autophagy. Through the analysis of DNA methylation throughout the genome of long-livers and their descendants, we identified epigenetically modulated genes and pathways that are potentially involved in the process of aging and longevity. Our results suggest that these populations were characterized by better preservation of DNA methylation status, slower cell growth / metabolism, and better control of signal transmission through epigenetic mechanisms (111). The longevity of the bioenergetic function due to mitochondrial hypertrophy,which can compensate for functional defects (112). In addition, healthy longevity has high levels of autophagy, as evidenced by higher levels of baclin-1 in serum compared with young patients with myocardial infarction and with healthy controls (113). An increase in autophagic activity was also observed in subjects belonging to families with exceptional longevity (114).
The corresponding phenomenon arises in relation to the inflammatory status, which is weakened in subjects after caloric restriction (115, 116) and high in long-livers (117-119). With aging, a state of mild and chronic inflammatory pathology (age inflammation) and an increased prevalence of a number of diseases, such as cardiovascular diseases, atherosclerosis, tumors, cognitive impairment, osteoarthritis and diabetes (120, 121), are observed. Consequently, the weakening of the chronic inflammatory status after caloric restriction is a beneficial effect. Centenarian long-livers show signs of inflammation, but at the same time seem to be spared from its harmful effects. This obvious paradox can be explained by the factthat long-livers have a complex and peculiar balance between pro-inflammatory and anti-inflammatory factors, which leads to a slower, more limited and balanced development of inflammation compared with the elderly, which are characterized by an ineffective response to counteracting chronic inflammation (120, 121).
These data suggest the general mechanisms for increasing life expectancy and postponing age-related diseases that are found in centenarians and mammals during a calorie restricted diet.
Opinion of the authors.
Preclinical models provided a deep insight into the aging process using consistent data that takes into account the role of the GH / IGF-1 / insulin system in modulating life expectancy. Although it is well known that insulin sensitivity and low insulin levels are associated with improved survival, there is some evidence that weakening the GH / IGF-1 axis can have a beneficial effect on increasing longevity in humans. However, it is still unknown what the optimal levels of IGF-1 are for life, to live longer and be healthier. In addition, the sensitivity of the IGF-1 receptor and the activation of the post-receptor pathway were not evaluated in most studies involving long-lived subjects. Consequently,It is not possible to determine the actual activation status of IGF-1 receptor signaling through a simple dose of circulating levels of IGF-1. This makes it difficult to determine pharmacological or environmental strategies aimed at this system to increase longevity and promote healthy aging. A comprehensive understanding of these aspects remains the main problem for identifying interventions aimed at slowing the aging of a person, and application in rehabilitation medicine. Future studies should assess the functional status of IGF-1 receptor signaling, including through transcription profiling and analysis of functional networks related to IGF-1 regulated genes, in long-lived subjects.This makes it difficult to determine pharmacological or environmental strategies aimed at this system to increase longevity and promote healthy aging. A comprehensive understanding of these aspects remains the main problem for identifying interventions aimed at slowing the aging of a person, and application in rehabilitation medicine. Future studies should assess the functional status of IGF-1 receptor signaling, including through transcription profiling and analysis of functional networks related to IGF-1 regulated genes, in long-lived subjects.This makes it difficult to determine pharmacological or environmental strategies aimed at this system to increase longevity and promote healthy aging. A comprehensive understanding of these aspects remains the main problem for identifying interventions aimed at slowing the aging of a person, and application in rehabilitation medicine. Future studies should assess the functional status of IGF-1 receptor signaling, including through transcription profiling and analysis of functional networks related to IGF-1 regulated genes, in long-lived subjects.and applications in rehabilitation medicine. Future studies should assess the functional status of IGF-1 receptor signaling, including through transcription profiling and analysis of functional networks related to IGF-1 regulated genes, in long-lived subjects.and applications in rehabilitation medicine. Future studies should assess the functional status of IGF-1 receptor signaling, including through transcription profiling and analysis of functional networks related to IGF-1 regulated genes, in long-lived subjects.
findings
A striking similarity has been described with respect to the endocrine profile between the long-livers and the subjects after a calorie restricted diet. The endocrine and metabolic adaptations observed in both models may represent a physiological strategy for increasing longevity due to slower cell growth / metabolism, slower loss of natural physiological reserve, transition of cell metabolism from cell proliferation to regenerative activity and reduction of the accumulation of aging cells. These mechanisms appear to be, at least in part, mediated by modulation of the GH / IGF-1 / insulin system.
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Giovanni Vitale, Giuseppe Pellegrino, Maria Vollery, and Leo J. Hofland. ROLE of IGF-1 System in the Modulation of Longevity: Perspective Front Endocrinol (Lausanne). 2019; 10:27
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