The only study published to date that specifically addresses the impact of an isolated primary alteration in insulin signaling on lifespan in mammals is a report of increased longevity of mice with disruption of the insulin receptor in its adipose tissue.Fat Insulin Receptor Knockout (“FIRKO”) mice have essentially normal appearance, food intake and fertility, are lean, insulin sensitive, and outlive normal (wild-type) animals by approximately 18%. Moreover, these animals are resistant to age-related and high fat dietinduced obesity and glucose intolerance. Consistently with reduced adiposity, adiponectin expression in white adipose tissue of FIRKO

mice is increased but unexpectedly, leptin levels are also elevated



The insulin/insulin-like growth factor 1 (IGF1) signalling pathway — a lifespan, metabolism and stress-resistance regulator — links neurodegeneration to the aging process. Thus, although a reduction of insulin signalling can result in diabetes, its reduction can also increase longevity and delay the onset of protein-aggregation-mediated toxicity. Here we review this apparent paradox and delineate the therapeutic potential of manipulating the insulin/IGF1 signalling pathway for the treatment of neurodegenerative diseases.



Some flies were fed mifepristone, a chemical copy of progesterone. This hormone activated a switch attached to dFOXO, which in turn repressed the normal insulin signals inside the cells. As a surprising result, insulin production was lowered throughout the body. These flies lived an average of 50 days – 18 days longer than flies whose insulin signals went unchecked. "We now know that insulin is a direct player in the aging process," Tatar says. "So the research fits some key puzzle pieces together. And it should change the way we think about aging." Tatar's research is part of a growing body of evidence linking low insulin levels to increased longevity. In recent years, scientists have found that mice and other animals live longer when they eat a low-calorie diet, which reduces insulin production. "Aging regulation is a complex physiological process of nutritional inputs, metabolic regulation and hormone secretion," Tatar says. "But we still have so many unanswered questions."





Thus, increased mitochondrial oxidative phosphorylation due to increased influx of nutrients in the absence of increased ATP consumption may be expected to increase mitochondrial O2•−production due to depletion of ADP availability and increased occupancy of electron carriers. Similarly, a reduction in mitochondrial number without a concomitant reduction in nutrient uptake will increase net substrate flux through the remaining mitochondria resulting in increased O2•− production per energy unit.



In fact, calorie restriction induces a reduction in the insulin signalling pathways (both through IGF-I and insulin), and this reduction in insulin signalling pathways is thought to be one of the primary mechanisms through which calorie restriction acts to increase lifespan.High blood insulin levels are usually the result of high blood glucose levels. So high levels of insulin signalling are a signal of high "nutritional state", and shift a cell's internal state towards increased levels of growth and decreased levels of repair. Increases in growth and decreases in repair = increases in waste products that accumulate within a cell and that ultimately cause aging at the cellular level.An increase in insulin levels usually causes an increases in protein synthesis and decreases in both proteolysis and autophagy through the pathway diagrammed below [1]. This is, as this will effectively increase the number of misfolded proteins that fail to degrade (one major factor in aging rate). In fact, decreased protein synthesis and increased autophagy are both associated with increased lifespan ().For a summary of its physiological effects, seeInsulin stimulates mTOR, and inhibition of mTOR by rapamycin is associated with the anti-aging effects of rapamycin (seeand).As a secondary pathway (see pathway below), insulin also inhibits FOXO1, and FOXO1 is involved in cellular stress resistance. Increased activity of the C. elegans homologue of FOXO1 (daf-16) is required for the 2x life extension caused by reducing IGF1 signalling through mutation of daf-2 (the C. elegans analogue of the IGF1 receptor - see).(figure fromFurthermore, insulin plays a key role in making organisms fatter, as it forces fat cells to take in circulating lipids (through increasing SREBP-1c activity). While accumulation of fat is important and doesn't necessarily cause aging in itself, it often increases inflammation levels, especially in an organism that is already metabolically compromised.See below figure.Artificial sweeteners basically "fool" the organism into anticipating that it is in a nutritional-rich state, which effectively causes it to increase its insulin levels (see), which basically result in both weight gain and metabolic syndrome (seeand, among many other links).Insulin is a huge reason why Type-II diabetes is so pernicious to health (and is associated with accelerated aging). People with type-II diabetes basically have higher-than-normal levels of both insulin and glucose. Ultimately, cells with too much insulin cannot stand all the insulin signalling anymore and become resistant to insulin [2]. This, in effect, makes higher levels of insulin necessary in order to cause reductions in glucose, which further elevates the blood glucose levels of diabetics, which makes them suffer all the blood vessel damage associated with high glucose levels. See diagram below for an illustration of insulin resistance from Lippincott's Biochemistry:One thing to note: C. elegans, fruit fly, and mouse mutants with knockouts in the insulin-like IGF-I factor pathway are known to have exceptionally increased lifespans [3].. Seefor a very good review.Also, see these following articles on insulin and aging:and this:[1]- Autophagy and Aging Review Article[2] In fact, some hypothesize that insulin resistance is actually a cell's last-ditchmeasure against excessive insulin signalling in the presence of high glucose levels - seeandInsulin resistance prevents too much glucose from entering the cell. If too much glucose enters the cell, then glycolysis can convert the glucose into glycolytic intermediates (like glyceraldehyde-3-phosphate) that can cause damage to proteins within the cell's cytosol (seeOne hypothesis is that cellular overnutrition (from too much glucose itself) could also create the mitochondrial oxidative stress that could presumably cause insulin resistance, as explained by the below quote:So in the presence of super-high levels of glucose, the cell becomes resistant to insulin in order to prevent significantly more glucose from coming into the cell (and ultimately causing oxidative stress through its downstream targets).Although glucose in the cell is more quickly converted into other endproducts (via glycolysis), these endproducts still represent a state of nutritional excess that ultimately increase mitochondrial oxidative phosphorylation and the formation of reactive oxygen species in the mitochondria.[3] I'm not yet aware of correlations between insulin and IGF-I yet.Some additional reading: