Mitogenic factors accelerate later-age diseases: insulin as a paradigm

SummaryCaloric restriction is the most effective non-genetic intervention to enhance lifespan known to date. A major research interest has been the development of therapeutic strategies capable of promoting the beneficial results of this dietary regimen. In this sense, we propose that compounds that decrease the efficiency of energy conversion, such as mitochondrial uncouplers, can be caloric restriction mimetics. Treatment of mice with low doses of the protonophore 2,4-dinitrophenol promotes enhanced tissue respiratory rates, improved serological glucose, triglyceride and insulin levels, decrease of reactive oxygen species levels and tissue DNA and protein oxidation, as well as reduced body weight. Importantly, 2,4-dinitrophenol-treated animals also presented enhanced longevity. Our results demonstrate that mild mitochondrial uncoupling is a highly effective in vivo antioxidant strategy, and describe the first therapeutic intervention capable of effectively reproducing the physiological, metabolic and lifespan effects of caloric restriction in healthy mammals.

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“…3c). Again, the results observed are similar to those seen in caloric restriction (Masoro et al ., 1992; Lev‐Ran, 1998).…”

Section: Resultsmentioning

confidence: 99%

Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity

Silva¹,

Cerqueira²,

Barbosa³

et al. 2008

Aging Cell

300

169

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“…Small elevations of circulating levels of IGFs or an increase in the IGFs/BPs ratio, especially at critical ages such as childhood and adolescence, may promote cancers that become clinically evident during adult life [134]. Hyperinsulinemia, a consequence of insulin resistance, may also play a key role in cancer promotion [135][136][137][138]. Hyperinsulinemia may act indirectly, by decreasing IGF-BP1 and IGF-BP2 levels and increasing IGF-I bioavailability [137], but it may also stimulate cancer cells directly through overexpressed IR-A and HR A .…”

Section: Concluding Remarks and Implications For Cancer Prevention Anmentioning

confidence: 99%

The Role of Insulin Receptor Isoforms and Hybrid Insulin/IGF-I Receptors in Human Cancer

Belfiore¹

2007

CPD

226

169

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This review will focus on the emerging role of the insulin receptor (IR) in cancer. Several epidemiological studies have shown that insulin resistance states, characterized by hyperinsulinemia, are associated with an increased risk for a number of malignancies, including carcinomas of the breast, prostate, colon and kidney. Recent data have elucidated some molecular mechanisms by which IR is involved in cancer. First, IR is overexpressed in several human malignancies. Interestingly, one of the two IR isoform (IR-A) is especially overexpressed in cancer. IR-A is the IR fetal isoform and has the peculiar characteristic to bind not only insulin but also IGF-II. Second, IR forms hybrid receptors with the homologous IGF-IR, which is also commonly overexpressed in cancer. These hybrid receptors containing IR-A hemidimers have broad binding specificity as they bind IGF-I and also IGF-II and insulin. By binding to hybrid receptors, insulin may stimulate specific IGF-IR signaling pathways. Overexpression of IR-A is, therefore, a major mechanism of IGF system overactivation in cancer. These findings may have important implications for both the prevention and treatment of common human malignancies. They underline the concept that hyperinsulinemia, associated with insulin resistance and obesity, should be treated by changes in life style and/or pharmachological approaches to avoid an increased risk for cancer. IR-A isoform and hybrid receptors should be regarded, therefore, as potential molecular targets for novel anti-cancer therapies.

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“…to them. Since obesity is a hyperinsulinemic condition, and since insulin is a potent mitogen, it is intriguing to consider its possible role as a mediator [44]. To appreciate the role of obesity as a provoking factor it is sufficient to compare the very low diabetes morbidity among the mostly slim Chinese in mainland China with the very high morbidity in their more overweight compatriots in Hong Kong, Singapore or the USA.…”

Section: Bulging Waistlines Of the Populations In Prosperous Countriesmentioning

confidence: 99%

Human obesity: an evolutionary approach to understanding our bulging waistline

Lev-Ran

2001

Diabetes Metabolism Res

Self Cite

131

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The unique worldwide spread of the human species and the remarkably long post-reproductive survival show that our genome permits excellent adaptation to vastly different environments. Moreover, the main scourges of later age, namely malignant growths and atherosclerosis, appear in humans later than in shorter-living animals. In recent years, excess weight and obesity have become mass phenomena with a pronounced upward trend in all developed countries. However, despite the detrimental effects of being overweight, these populations live longer than ever, which in part may be explained by the availability of better medical treatment. The prevalence and predicted further spread of obesity can be understood in the light of evolution. In all animal species energy metabolism is asymmetric with energy accumulation ('thrifty genotype') being the necessary condition of survival during hard times. For humans, which are no different to other animals in this respect, this genetic programming was necessary for survival because during the course of history, including the recorded history in the more developed Middle East, Europe or China, there was never a long period of uninterrupted food abundance, whereas famines were regular and frequent. Therefore fat accumulation, when food was available, meant survival at times of shortage, while the possible detrimental effects of overindulgence in food and being overweight expressed in unrealistically old age were irrelevant. It is the central, mostly intra-abdominal fat (in both humans and animals) that is more medically important than the subcutaneous truncal fat, and the accumulation of both types of fat is conditioned by high food consumption; therefore it is a historic novelty for human populations. In contrast, lower-body fat in human females is unique in the animal kingdom: it is much less metabolically active, it is of much lower pathologic significance than central fat, and it is programmed to be mobilized mostly during pregnancy and lactation. In view of all this, norms of desired weight should be based on hard mortality and morbidity statistics and not on theoretical, esthetic or fashion considerations. By this criterion, the upper limit of desirable weight is likely to be body mass index (BMI) 27 or 28, but specified for different populations (sex, race, ethnic origin); moreover, with aging, the detrimental effects of obesity diminish and finally disappear. Risks of other pathologies related to obesity (e.g. diabetes, hypertension and coronary disease) are also population-specific. However, total fatness, measured by BMI, is insufficiently sensitive as a risk factor, and fat distribution (upper-body versus low-body type, as reflected by waist circumference and waist:hip ratio) plays at least as prominent a role. Therefore the detailed norms, not yet available, should take into account both general obesity and fat distribution and be specific for different populations. Since long-term weight loss in adults is rarely achievable, public health measures should be aggressively d...

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Mitogenic factors accelerate later-age diseases: insulin as a paradigm

Cited by 17 publications

References 109 publications

Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity

Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity

The Role of Insulin Receptor Isoforms and Hybrid Insulin/IGF-I Receptors in Human Cancer

Human obesity: an evolutionary approach to understanding our bulging waistline

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