PUTTING IT ALL TOGETHER: Insulin/IGF-1 axis, mTOR, and Inflammation
Life spans of lower animals can be massively extended by blocking a recently discovered gene called TOR (Target Of Rapamycin, rapamycin is a soil bacteria antibiotic). mTOR (mammalian TOR) also functions in a similar manner in humans and other mammals but without as large a benefit when blocked. Insulin and TOR gene complexes are both elevated in response to nutritional abundance. Insulin informs the whole body of nutrient abundance and TOR acts at a single cell level to sense insulin and nutrients and coordinates use of these nutritional resource level inside the cells. Elevated insulin levels elevate TOR levels. Elevated TOR levels decrease the removal of damaged proteins by a process called autophagy and it is likely (along with insulin) is also involved in the elevation of NFkB inflammation that accompanies the last half of human life. This rising inflammation is responsible for the development of almost all of our late life age related diseases (cardiovascular (including stroke), types 2 diabetes, dementia's (Alzheimer's), and various hypertension, etc.). Over stimulation by insulin and then TOR lead to cellular over activation that un- coordinates the needed tissue/organ functions and induces all manner of age associated diseases. High levels of free radicals can initiate and aggravate most disease(s) conditions, but no combinations of "free radical destroying" antioxidants has led to a change in the intrinsic rate of aging. Insulin, NFkB driven Inflammation, and TOR gene complex elevations appears to be responsible for this intrinsic rate of aging. If we wish to change this intrinsic rate of aging, we must lower insulin, Inflammation, and TOR gene complex activations. This partly explains the 20-30% extensions above otherwise maximal life spans in calories restricted animals. These calorie restricted animals have very low insulin, lower inflammatory effects, and lower TOR activations due to lower nutrient abundance. It also explains why calorie restricted animals have lower levels of total protein oxidation over life span (better autophagy) much like regular taking out or recycling of trash). Nutritional abundance caused elevation of TOR gene activity blocks the normal cell scavenging of damaged components and intracellular parasites for disassembly & recycling(called autophagy). We have very limited means of affecting TOR gene complex, as rapamycin is also a profound suppressor of immunity (dangerous !). We do have numerous ways to lower Insulin gene complex activation and inflammation by choice of diet, by cooking procedures, by antioxidants, by limitation on total caloric intake, by exercise, by higher rates of burn off of calories, and by several different drugs. Lowering Insulin levels will correspondingly lower mTOR gene activation and lower our inflammatory driven age-associated diseases. This will promote a Longer Healthy Life.
mTor (mammalian TOR) is responding indicator to our nutritional status, and makes decisions about how resources will be used. How these allocation decisions were made was not very clear. However, work on a gene called TOR has allow us to integrate a variety of understandings about how cells make decisions about development, growth, and aging. What has been found is a higher level of TOR gene activity (in a broad sense of the TOR complex of genes) leads to a shorter life. Naturally, TOR is sensitive to the level of insulin and increases in activity along with increasing insulin exposure. It is also sensitive to the ATP levels created by the mitochondria.
mTOR pathway is influenced by the intracellular concentration of ATP, independent of the abundance of amino acids, and that mTOR itself is an ATP sensor. Mammalian TOR: a homeostatic ATP sensor. Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC, Thomas G. Science 2001 Nov 2;294(5544):1102-5 http://ncbi.nim.nih,gov/pubmed/11691993
TOR GENE AND THE CELLULAR ALLOCATION OF RESOURCES
mTor (mammalian TOR) is responding indicator to our nutritional status, and makes decisions about how resources will be used.The gene complex associated with the TOR gene in mammals senses growth factors (systemic signals to whole body like insulin) and intracellular levels of nutrients (amino acids, etc.) and oxygen levels, ATP levels, stress levels, and integrates these factors into allocation of what proteins are synthesized and how much in each cell. TOR is involved in this process from fertilization onward, and is a highly conserved gene response in all of animal life. Cell growth and division as well as our early development are also under this INSULN -TOR controls. TOR gene was named after Target Of Rapamycin, with Rapamycin being a potent anti-fungal compound found in a soil bacteria from Easter Island. Rapamycin despite it's powerful anti-fungal activity, could not be used as an anti-fungal in most animals because it massively inhibited the immune system of animals. To test effects on life span, old mice that were isolated against infections and given Rapamycin were found to live some 9-14% longer than expected. This result paralleled studies finding a much higher life extension in lower invertebrates with Rapamycin lowered TOR levels. This discovery and it's integration with the understanding of life extension by calorie restricted animals and centenarians has led to a very major advance in the field of aging.
The forming 'paradigm' is that low insulin levels (signaling low levels of glucose (sugar) and amino acids (from proteins) in the CR animals lead to low TOR levels and this delays the process of aging. More accurately, it might be said that low TOR levels leads to a postponement of age associated diseases from which most people die (cancer, heart disease, etc). Since this integration mediates a very wide variety of cellular processes with external hormonal signals and immediate nutritional status, energy status, cell stress levels, the process of integration is quite complex. Rather than cover all the complicated and not yet fully agreed upon details (REF1, REF2, REF3, REF4 ), we will concentrate on how the levels of insulin interact with TOR gene complex. We already know multiple ways to lower insulin levels in our body, for one example by having a very gradual delivery of sugars from our carbohydrate foods by eating slow to release complex sugars (starches) instead of simple sugars that stimulate insulin to higher levels.
The INSULIN/TOR over activation formulation also provides an understanding of why oxidized protein increase with age. The process of breaking down damaged proteins to recycle most amino acids and also disassembling damaged cell organelles (like mitochondria that have had accumulated mutations and no longer are good energy producers) is called AUTOPHAGY. Autophagy is driven by lower nutrient levels, especially lower amino acid levels, and thus lower INSULIN/TOR levels. Note that this also provides a means to reverse this, by lowering intake of food and particularly amino acids for a substantial period. CR animals have lower oxidized proteins than ad libitum fed, because they have daily periods of very low food intakes. Not all tissues in CR animals benefit equally, but all CR tissues appear to benefit with lesser rises in oxidized proteins.
Autophagy delivers cytoplasmic material and organelles to lysosomes for degradation. ... Autophagy functions as a stress response that is upregulated by starvation, oxidative stress, or other harmful conditions. The magnitude of autophagosome formation is tightly regulated by intracellular and extracellular amino acid concentrations and ATP levels via signaling pathways that include the nutrient sensing kinase TOR. Autophagy functions as a stress response that is upregulated by starvation, oxidative stress, or other harmful conditions. Remarkably, autophagy has been shown to possess important housekeeping and quality control functions that contribute to health and longevity. Autophagy: a lysosomal degradation pathway with a central role in health and disease. Eskelinen EL, Saftig P Biochim Biophys Acta. 2009 Apr;1793(4):664-73 < current author's emphasis >
The age-associated increase in oxidative damage in ad libitum-fed mice is attenuated in mice fed calorically restricted (CR) diets... Overall, the current findings indicate that changes in the level of caloric intake may reversibly affect the concentration of oxidized proteins and sufhydryl content. In addition, chronic restriction of caloric intake also retards the age-associated accumulation of oxidative damage. The magnitude of the reversible and chronic effects appears to be dependent upon the tissue examined and the nature of the oxidative alteration. Reversible Effects of Long-Term Caloric Restriction on Protein Oxidative Damage Michael J. Forster, Barbara H. Sohal and Rajindar S. Soha The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 55:B522-B529 (2000) < current author's emphasis >
A properly working system of autophagy may also protect us against the afore mentioned rise in mitochondrial DNA damage. A profound age related increase in mutations and deletions occurs primarily in our mitochondrial DNA but not our nuclear DNA (our primary genetic material in the nucleus of the cell). Autophagy would "retire for recycling" mitochondria that have reduced energy production due to this mitochondrial DNA damage. Absent autophagy "retirement", the damaged mitochondria may be at a competitive advantage in reproduction and populate our cells with very poor energy factories that are the primary purpose of mitochondria in our cells.
How does Over activation of Signal Pathways by TOR kill us? I'll let Blagosklonny answer that question.
"TOR stimulates translation < protein synthesis >. This could explain why inhibition of translation < partial inhibition of protein synthesis in cell > increases lifespan.70,71 TOR inhibits autophagy (self-eating by lysosomes).31 < breaking down to components of damaged proteins and dysfunctional organelles like dysfunctional mitochondria and recycling the useful amino acids - lowers the age accumulating oxidized proteins > And inhibition of autophagy is involved in aging.72-75 TOR causes cell mass growth (cell hypertrophy), stimulates ribosomal synthesis, induces accumulation of aggregation-prone proteins, increases growth factors (GF) secretion and causes resistance to GF < growth factors like IGF-1 = insulin like growth factor-1 > and insulin. In brief, TOR causes cellular hyperfunction. This hyperfunction secondarily causes cellular (not molecular) damage and organ failure. On the organismal level, these cellular hyperfunction, hypertrophy and hyperplasia are manifested as age-related diseases. These diseases culminate in cellular (not random molecular) damage, including cell death and organ failure... FSH hyperproduction with age causes follicular depletion in the ovaries, known as menopause... overactivation of TOR in fat and skeletal muscle causes insulin resistance. Insulin resistance causes compensatory activation of beta-cells in the pancreas. This hyperactivation ultimately results in the failure of beta-cells and type II diabetes... And the most dramatic example is cancer, which causes failure of the organ, where tumors grow. Obviously, there is no “weakening” of cancer cells. In contrast, the problem is that they are too robust... Mammals do not die from healthy aging, they die from age-related diseases. TOR is involved in all of them... TOR limits lifespan by accelerating age-related diseases... These diseases terminate lifespan in mammals, before the accumulation of molecular damage may reach clinical threshold. Both inhibition of autophagy and signal-resistance are a consequence of hyper-active TOR... Furthermore, it explains why autophagy is insufficient. It is a consequence of over-stimulation of the TOR pathway... autophagy is such a fundamental cellular function that its inhibition would shorten lifespan, even if it were not playing any role in aging... It has been shown that increased TOR signaling enhances sensitivity of the whole organism to oxidative stress.104 In other words, decreased TOR signaling correlates with resistance to oxidative stress. Therefore, selection for resistance to oxidative stress should select for low TOR activity... ROS < reactive oxygen species = free radicals + Peroxide H2O2 > and oxygen activate TOR... Needless to say, the insulin signaling activates the TOR pathway. " Aging: ROS or TOR. Blagosklonny, MV Cell Cycle. 2008 Nov 1;7(21):3344-54 < clarification and emphasis by current author >
This last concatenated paragraph is a virtual list of most things we see going wrong with age. Over stimulation via the Insulin/TOR axis is involved in all of them.
spite of this, I am not a great fan of this explanation of mistaken allocation
of resources to never to occur divisions. I will elaborate on this shortly.
I would argue that the main axis of human (& mammalian) aging is a combination of activation of INSULIN/IGF-1, chronic inflammatory NFkB production, and TOR pathways that drive aging and that ROS (Radical Oxygen Species= free radicals + H2O2 hydrogen peroxide) levels can also be part of this picture. Blagosklonny also argues for a benefit to lowering ROS levels as adding to life span after the lifespan gains of lowering TOR. I see no reason to wait till then to lower ROS with antioxidants in our foods RIGHT NOW.
If TOR elevation is so pro-aging, why can't we just use Rapamycin inhibition of TOR gene activity to gain longer life?
Rapamycin given to very elderly mice (90% mortality already, only 10% remaining alive for the experiment) was found to have a life span increase of 14% in females and a 9% in males. The same experiment with mice at about half this age is still in progress, we are still waiting on the results..
One possible reason this technique of Rapamycin inhibition of TOR may have some problems is that a depressed immune system will not do a good job of taking out forming cancers. Cancers can arise not only from the gradual TOR elevation but also due to persistent local irritation/inflammation/high Free Radicals. When rapamycin is taken over a long period of life the immune system is greatly inhibited. This inhibition may have negative consequences on cancer rates. CR rats generally have half the cancer rates of their ad libitum controls, so clearly the influence of low insulin is very beneficial to limiting cancer rates.
Another drug that lowers TOR does so through it's effect on insulin levels. Metformin is a drug used to increase insulin sensitivity (thus lowering insulin levels). Metformin also indirectly inhibits TOR gene . This explains the findings of an 8-10% maximum life span extension with metformin in mice.
CR has been found to confer up to 83% increase in mean life span , and routinely delivers some 20-30% increase above the species maximum life span. If this assessment of importance of lowering insulin levels is correct, we can do that in place of rigorous CR.
It is possible that some clever biochemistry/pharmacology can untangle the rapamycin immune suppression from the repression of TOR activity. This would potentially permit use of of this modified (or redesigned from scratch) drug to extend our lives. For now, this does not exist. Your ability to lower your systemic insulin levels with consequent lowered TOR levels EXISTS RIGHT NOW. No evidence exists to question the benefit of lower but effective insulin levels RIGHT NOW. TOR elevation can be rapidly reversed by lowered insulin levels, but we have as yet no evidence that drug lowering of TOR (by rapamycin) can massively lower insulin levels. Insulin is the mother hormone of animal life. We would be wise to undertake lowering of our insulin levels by simple actions like eating chewy but not crunchy complex carbohydrate grains in place of simple sugars. This would so much lower the rate of delivery of glucose after a meal, that we would have massively lower insulin exposure. As we will detail in the DIET, ANTIOXIDANT, and EXERCISE sections, this is only one of multiple ways we can non-medically lower our insulin exposure.
Do Insulin or TOR levels have more effect?
Insulin is a systemic (whole body) informer of nutrient status to all cells and tissues and mTOR is the intracellular coordinator of this information. mTOR also evaluates an individual cell's stress levels and cellular energetic status and amino acid levels. Both TOR and Insulin are important but insulin is the whole systemic informant (WHOLE BODY INFORMER). Systemic level applies to all cells, where TOR will act as needed in specific local cell situations. Lowering systemic insulin levels will lower TOR levels absent some particular localized cellular trauma. We can directly control and lower our insulin levels. We currently have only a few means other than Rapamycin to lower TOR, and that has some untoward consequences as mentioned above. Some other compounds like curcumin from Turmeric can also lower mTOR with little side effects.
In animals, nutritional status is monitored and signaled at both the cellular and systemic levels. The main mediator of cellular nutrient sensing is the protein kinase TOR (target of rapamycin). TOR receives information from levels of cellular amino acids and energy, and it regulates the activity of processes involved in cell growth, such as protein synthesis and autophagy. Insulin-like signaling is the main mechanism of systemic nutrient sensing and mediates its growth-regulatory functions largely through the phosphatidylinositol 3-kinase (PI3K)/AKT protein kinase pathway. Other nutrition-regulated hormonal mechanisms contribute to growth control by modulating the activity of insulin-like signaling. The pathways mediating signals from systemic and cellular levels converge, allowing cells to combine information from both sources. Regulation Mechanisms and Signaling Pathways of Autophagy Ville Hietakangas & Stephen M. Cohen Annual Review of Genetics Vol. 43 (Volume publication date December 2009) (doi:10.1146/annurev-genet-102108-134815) < Current author's emphasis>
There is one final explanation not covered above, nor much discussed in the literature (that has mainly come from TOR studies of lower eucaryotes that may or may not die as do vertebrates, humans included). Remember that TOR gene was discovered by the using the anti-fungal natural product from Easter Island called rapamycin What disappointed the drug industry at that point was that mammals treated to rapamycin experienced a profound suppression of normal immunity. So instead of anti-fungal, rapamycin is now a useful tool for transplant patients who need to have a suppressed immune system or they reject foreign tissue (Kidney, heart, transplants,etc.). Clearly, TOR can massively suppress the immune system. A question not asked is: CAN ELEVATIONS OF TOR GENE BY ELEVATED INSULIN LEVELS/FOOD EXCESS ELEVATE THE INFLAMMATION PART OF THE IMMUNE SYSTEM, PERHAPS INAPPROPRIATELY?
In the case of aging, what we see for almost all the major killers of humans (cancer, heart and circulatory diseases, Type 2 diabetes mellitus, autoimmune diseases,many neural dementia's, etc.) and other mammals (probably all vertebrates) are INFLAMMATORY ACCELERATED AGE ASSOCIATED DISEASES that lead to physiological deterioration and then to death. The easiest way to block inflammation is to inhibit or decrease the DNA binding of Nuclear Factor kappa B (NFkB). If the elevated INSULIN / TOR combination can lead to the higher DNA binding of NFkB binding to increase CHRONIC INFLAMMATORY EVENTS, we have a mechanism. These chronic inflammatory events then act along lines of genetic predisposition, lifestyle characteristics (little or no exercise, bad behaviors like smoking, failure to eat sufficient Fresh vegetables, etc.), or particular critical organ weakness (the weakest link...), then we can unite a very large set of human data experience with how humans (all vertebrates?) are observed in die in general. IS IT POSSIBLE THAT ELEVATED INSULIN / TOR GENE ACTIVITY LEADS TO ELEVATED NFkB BINDING & CHRONIC PRODUCTION OF INFLAMMATORY CYTOKINES THAT ELEVATE INFLAMMATION (accelerating these age-associated diseases)? THIS CAN BE EITHER INDIRECTLY BY EXCESS FOOD DRIVEN RADICAL INCREASE OR INDIRECTLY BY A GENERALIZED EXCESS FOOD DRIVEN OMENTAL (BELLY) FAT or food AGE's, INFECTIONS, etc. Rapamycin inhibition of TOR gene does not block NFkB DNA binding directly, but rather makes T & B cells insensitive to elevated levels of activating cytokines like IL-2 and others - thus inhibition TOR gene prevents specific immunity without preventing inflammation. If INSULIN / mTOR actions or chronic inflammatory elevation arise with age, this could explain the what drives the epigenetic alterations that give rise to the diseases of age. This suggests that merely forcing an elevated chronic DNA binding of NFkB (NFkB activation) to cause higher inflammation would suffice to create the epigenetic changes needed ot initiate all the inflammatory driven diseases of age (despite observed different mechanisms of age-associated diseases). This mid-age inflammatory boost that worsens would also explain the meaning or the Gompertz acceleration of the death rate with age (a doubling of the death rate every 8 years for humans) and tie together the long suspicions of immune system involvement in human longevity. This question will be covered in more detail in the SUBSCRIBER ONLY LONGENITY PDF. You may subscribe by clicking on this SUBSCRIBE link or you may use the menu in the upper left to choose SUBSCRIBE.
What we have learned in this section is that rapid delivery of nutritional support drives "over stimulation" of the Insulin/IGF-1 and mTOR control systems along with the ensuing disease creating and accelerating chronic inflammation that appears to be able to stimulate harmful epigenetic changes that set up and generate conditions for the various age-associated diseases. Thus, this nutritional excess "over stimulation" of the Insulin/IGF-1 & mTOR control systems are the principal causes, and set the rate of our human and general mammalian aging (absent infections, etc.). this combines with genetic and environmental influences to select which of the of age associated diseases develops first as well as setting the timing of onset and rate of development of these diseases. Extending the healthy period of life involves slow nutritional delivery of just enough nutrition to blunt the elevations of Insulin-IGF-1 and mTOR along with lessening the development of a rise in chronic inflammation.
"several studies in humans have shown that longevity is associated with a significant improvement in glucose handling - mainly, a rise in insulin sensitivity and a decline in plasma insulin-like growth factor I levels" Metabolic Journey to Healthy Longevity Michelangela Barbieri, Virginia Boccardi, Michela Papa, Giuseppe Paolisso Horm Res 2009;71 (Suppl. 1):24-27 http://www.ncbi.nlm.nih.gov/pubmed/19153500
While research on CR in humans is still at an early stage, a modest amount of information has accumulated. Because it is not feasible to conduct studies of the effects of CR on longevity in humans, surrogate measures have to be used. Preliminary information obtained using this approach provides evidence that CR provides a powerful protective effect against secondary aging in humans. This evidence consists of the finding that risk factors for atherosclerosis and diabetes are markedly reduced in humans on CR. Humans on CR also show some of the same adaptations that are thought to be involved in slowing primary aging in rats and mice. These include a very low level of inflammation as evidenced by low circulating levels of c-reactive protein < a five fold drop in C-reactive Protein ! > and TNFalpha, serum triiodothyronine levels at the low end of the normal range, and a more elastic "younger" left ventricle (LV), as evaluated by echo-doppler measures of LV stiffness. Caloric restriction in humans. Holloszy JO, Fontana L. Exp Gerontol. 2007 Aug;42(8):709-12. Epub 2007 Mar 31. http://www.ncbi.nlm.nih.gov/pubmed/17482403
We can lower the elevation of the Insulin/IGF-1 axis, mTOR gene, and the ensuing rising chronic inflammatory sequence in humans by food components in our historic diet that have been used by humans for thousands of years ! Other specific components of our normal diet are able to rapidly undo the epigenetic changes created by this elevation sequence of unwise actions. See Longevity PDF for SUBSCRIBERS.