Vladimir N. Anisimov, MD

Disclosures

Cancer Control. 2007;14(1):23-31. 

In This Article

Interaction of Aging and Carcinogenesis: Physiologic Level

The potential link between aging and insulin/IGF-1 signaling has attracted substantial attention during recent years based on evidence such as the age-related increase in the incidence of insulin resistance and type 2 diabetes in accelerated aging syndromes or lifespan extension by caloric restriction in rodents. Concomitant reduction in plasma insulin and plasma glucose levels, which implies increased sensitivity to insulin, emerges as a hallmark of increased longevity.[49] Hyperglycemia is an important aging factor involved in the generation of advanced glycosylation endproducts (AGEs).[50] There is evidence that hyperinsulinemia favors the accumulation of oxidized proteins by reducing their degradation as well as facilitating protein oxidation by increasing the steady-state level of oxidative stress.[50] Untreated diabetics with elevated glucose levels suffer many manifestations of accelerated aging such as impaired wound healing, obesity, cataracts, and vascular and microvascular damage.[10] Hyperinsulinemia is an important factor not only in aging but also in the development of cancer.[10,51]

Intensive investigations in Caenorhabditig elegans since the 1990s, which have identified insulin signaling components including daf-2, age-1, and daf-16 as the genes whose mutations lead to lifespan extension, have shed new light on the molecular mechanisms underlying aging.[49] In Drosophila melanogaster, the mutations of genes operating in the signal transduction from insulin receptor to transcription factor daf-16 (age-1, daf-2, CHICO, InR, etc) are strongly associated with longevity.[52] It was demonstrated that FKHR,FKHRL1 and AFX,which are mammalian homologs of daf-16 forkhead transcription factor, function downstream of insulin signaling and akt/PKB under cellular conditions.[53]

InR and daf-2 are structural homologs of tyrosine kinase receptors in vertebrates that include the insulin receptor and the insulin-like growth factor type 1 receptor (IGF-1R). It was shown that in vertebrates, the insulin receptor regulates energy metabolism whereas IGF-1R promotes growth. At least three genes (Pit1,dw Prop1,dw and Ghr) have been identified in which knockout led to dwarfism with reduced levels of IGF-1 and insulin and to increased longevity.[49] In Snell and Ames dwarf mice, sexual maturation is delayed, and few males are fertile while females are invariably sterile. These mice as well as Ghr-/- knockout mice have significantly reduced glucose levels and fasting insulin levels, decreased tolerance to glucose, and increased sensitivity to insulin, which appears to be combined with reduced ability to release glucose in response to an acute challenge.[49]

Hsieh et al[54,55] recently provided strong support for the role of the insulin/IGF-1 signaling pathway in the control of mammalian aging and for the involvement of this pathway in the longevity of IGF-1 deficient mice.[54,55] It was shown that in the Snell dwarf mice, growth hormone deficiency led to reduced insulin secretion and alterations in insulin signaling via InR®, IRS-1, or IRS-2, and P13K affects genes involved in the control longevity. The authors concluded that the Pit1 mutation might result in physiologic homeostasis that favored longevity.

Reduction in both glucose and insulin levels as well as an increase in the sensitivity to insulin are well documented responses to caloric restriction in rodents and monkeys.[56,57] It was shown that improved sensitivity to insulin in calorie-restricted animals is specifically related to reduced visceral fat.[58] Ghr--/- mice have a major increase in the level of insulin receptors,[59] while Ames dwarf mice have a smaller increase in insulin receptor and substantially increased amount of insulin receptor substrates IRS-1 and IRS-2.[60] The development of tumors in Ames dwarf mice was postponed and the incidence was reduced as compared to the control.[61]

The crucial mediators of the effect of caloric restriction are low levels of insulin and IGF-1 and an increase insulin sensitivity in rodents[62] and monkeys.[63] Many characteristics of these long-lived mutants and growth hormone receptor knockout mice resemble those of normal animals exposed to caloric restriction. These characteristics include reduced plasma levels of IGF-1, insulin, and glucose, with the consequent reductions in growth and body size, delayed puberty, and significantly increased sensitivity to insulin action.

Holzenberger et al[64] inactivated the Igf1r gene by homologous recombination in mice. Igf1r-/- mice died early in life, whereas heterozygous Igf1r +/- mice lived on average 26% longer than their wild-type littermates. These mice did not develop dwarfism, and their energy metabolism was normal. Food intake, physical activity, fertility, and reproduction were also unaffected in Igf1r +/- mice. These mice and the embryonal fibroblasts derived from them were more resistant to oxidative stress than controls. The spontaneous tumor incidence in the aging cohort of Igf1r +/- mice was similar to that in wild-type controls. At the molecular level, insulin receptor substrate and the p52 and p66 isoforms of Shc, both main substrates of the IGF-1 receptor,showed decreased tyrosine phosphorylation p66Shc-mediated cellular responses to oxidative stress. Two main pathways -- the extracellular-signal regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K)-Akt pathway -- were downregulated in Igf1r +/- mice.

Several years ago, the use of biguanide antidiabetics was suggested as a potential antiaging treatment.[65] The antidiabetic drugs phenformin (1-phenylethylbiguanide), buformin (1-butylbiguanide hydrochloride), and metformin (N,N-dimethylbiguanide) reduced hyperglycemia, improved glucose utilization, reduced free fatty acid utilization,gluconeogenesis, serum lipids, insulin, and somatomedin, reduced body weight, and decreased metabolic immunodepression in both humans and rodents.[10,66,67] Phenformin is not used in clinical practice today due to its side effects (mainly lactic acidosis) observed in patients with noncompensated diabetes. During more than 10 years of experience of phenformin administration to patients without advanced diabetes,Dilman[10] observed no cases of lactic acidosis or any other side effects. Nevertheless, we believe that the analysis of results of long-term administration of this drug as well as other antidiabetic biguanides (buformin and metformin) to nondiabetic animals is important in understanding the links between insulin and longevity.

Treatment with antidiabetic biguanides prolonged the mean lifespan of female mice and rats.[68,69,70,71] It was found that metformin significantly increases the lifespan of rats (G. S. Roth, PhD, personal communication, 2001). Spindler[72] found that metformin treatment reproduced the specific changes in gene expression produced by long-term calorie restriction.

The anticarcinogenic effect of antidiabetic biguanides has been demonstrated in several models of spontaneous and induced carcinogenesis. Treatment with phenformin normalized glucose tolerance and serum insulin and IGF-1 levels in rats exposed to intravenous injections of NMU, and it inhibited mammary carcinogenesis in these animals.[69,71] Treatment of rats with 1,2-dimethylhydrazine (DMH) caused a decrease in the level of biogenic amines, particularly of dopamine in the hypothalamus, a decrease in glucose tolerance, and an increase in the blood level of insulin and triglycerides. Administration of phenformin restored immunologic indices and inhibited DMHinduced colon carcinogenesis.[69,71,73]

Postnatal treatment with biguanides started from the age of 2 months significantly inhibited the development of malignant neurogenic tumors in rats transplacentally exposed to NMU or NEU.[69,71,73] In hamsters fed high fat, treatment with N-nitrosobis-(2-oxopropyl) amine was followed by the development of pancreatic malignancies in 50% of cases, whereas no tumors were found in the hamsters treated with both the carcinogen and the metformin.[74]

Thus, an anticarcinogenic effect of antidiabetic biguanides has been demonstrated in relation to spontaneous carcinogenesis in mice and rats, in different models of chemical carcinogenesis in mice, rats, and hamsters, and in radiation carcinogenesis model in rats. Phenformin administered orally to rodents potentiated the antitumor effect of cytostatic drugs on transplantable tumors.[75]

The comparative study of 10-year results of metabolic rehabilitation (including a restricted fat and carbohydrate diet and treatment with antidiabetic biguanides) of cancer patients has shown significant increase in the survival of breast and colorectal cancer patients, an increase in the length of cancer-free period, and a decrease in the incidence of metastasis compared with control patients.[10,67] In humans with type 2 diabetes,taking metformin may be associated with reduced cancer risk.[76,77]

Antidiabetic biguanides inhibit fatty acid oxidation, inhibit gluconeogenesis in the liver, increase the availability of insulin receptors, inhibit monoamine oxidase, increase sensitivity of hypothalamopituitary complex to negative feedback inhibition, and reduce excretion of glucocorticoid metabolites and dehydroepiandrosterone- sulfate.[10] These drugs have been proposed for the prevention of the age-related increase of cancer and atherosclerosis and for retardation of the aging process.[10,67] It has been shown that administration of antidiabetic biguanides into patients with hyperlipidemia lowers the level of blood cholesterol, triglycerides, and ®-lipoproteins. It also inhibits the development of atherosclerosis and reduces hyperinsulinemia in men with coronary artery disease. It increases hypothalamopituitary sensitivity to inhibition by dexamethasone and estrogens, causes restoration of estrous cycle in persistent-estrous old rats, improves cellular immunity in atherosclerotic and cancer patients, and lowers blood IGF-1 levels in cancer and atherosclerotic patients with type IIb hyperlipoproteinemia.[10] Data on the antioxidative effect of biguanides[78] and their neuroprotective activity are available.[79] It was shown that biguanides inhibit complex I of the respiratory chain in mitochondria, which leads to an activation of physiologic intracellular inhibition of mitochondrial respiration. [80] Biguanides stimulate a protein kinase cascade inhibiting an expression of transcription factor SREBP-1. An activation of this factor with cholesterol leads to an increase in transcription of genes coding lipogenesis enzymes and to suppression of free fat acids oxidation. Thus, stimulation of uptake of glucose in tissues by biguanides inhibits lipogenesis and activates oxidation of FFA.[81] It was shown also that in vivo biguanides inhibits appetite[82] and serum levels of leptin and IGF- 1.[83] It was suggested that biguanides regulate energy balance of the organism at the fat tissue level.[84] In general, the effects of biguanides seem similar to those of calorie restriction, and similar mechanisms are involved in the effects of calorie restriction and biguanides on lifespan and tumorigenesis.

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