The Hallmarks of Aging: Deregulated Nutrient SensingTo understand studies on nutrient sensing in the context of aging, let’s introduce four key protein groups. In this post, we’ll explore the pathways they help control and how they affect aging. These key proteins are IGF-1, mTOR, sirtuins, and AMPK 2. We call these proteins “nutrient sensing” because nutrient levels influence their activity2.   IGF-1 and the IIS pathway: The BasicsInsulin like growth factor (IGF-1) inhibits the secretion of growth hormone (GH) by binding to a special receptor on the surface of a cell1.  Like insulin, IGF-1 takes part in glucose sensing. Both it and insulin are part of the aptly named “insulin and insulin like growth factor” (IIS) pathway 2.Attenuation of the IGF-1/GH pathway (IIS) appears to improve lifespan in several model organisms1. For example, PI3K mice, which have a weakened IIS pathway, live longer2.  Additionally, FOXO, a transcription factor (a protein that affects the production of RNA), lengthens lifespans in worms and fruit flies by attenuating IIS signalling2. In other studies, IGF-1 improves healthspan even when it does not lengthen lifespan2There’s also evidence of a harmful impact when IGF-1 activity is high. Higher levels of IGF-1 are associated with increased risk of some types of cancers1. This increased cancer risk might be due to IGF’s ability to promote pathways that result in increased cell production1. IIS and the Not-So-Basics    IGF-1 expression and the IIS pathway are a bit of a paradox. Since it looks like turning down the IIS pathway promotes longevity, you might expect the IIS pathway to be very active in old organisms. It looks like high IIS ages us, after all.  However, that’s not the case. In both accelerated and normal aging models we see the IIS pathway decreases2.One explanation for this weirdness is that it’s a last act measure of the organism to increase its own lifespan. Yet, this short term decrease in IIS activity can be harmful. In fact, it is so harmful that IGF-1 supplementation is beneficial2. What this seems to point to is a dichotomy concerning the expression of IIS.  Overall, it looks like turning down the IIS pathway is good over the long term for longevity. This might be because it causes the reduction of metabolism and cell growth which lessens wear and tear2.  However, the body’s attempt to do the same in later life, goes too far and too late to be truly beneficial.How IGF-1 affects human lifespan is still fuzzy as well1. On one hand, there is indication of a longevity effect with reduced IGF-1 activity in those with Laron syndrome(who don’t have functional growth hormone receptors), female nonagenarians, and extremely long lived people1.  Yet, the epidemiological data is not clear enough to be conclusive on IGF-1’s effects on humans1. This is partially due to the difficulty of structuring epidemiological studies on IGF-1 when so many external factors like nutrition can confound results1.mTORmTOR is composed of the mTORC1 and mTORC2 protein complexes. It senses amino acids 2 and is associated with nutrient abundance2. It is a kinase, which means it adds phosphates to molecules2. mTOR is a champion regulator of anabolic metabolism2, the process of building new proteins and tissues. In this way, how it functions is similar to the IIS pathway2. At any given moment the metabolism is either breaking down old parts (catabolism) or building new ones (anabolism). Both mTOR and the IIS are part of the anabolic side of metabolism.Lower activity of mTOR lengthens lifespan in model organisms such mice, yeast, worms, and flies2. Along those lines,  mTOR activity increases in the hypothalamus of aged mice which promotes late life obesity. With rapamycin, an inhibitor of mTOR, these effects are ameliorated2. As is the case with, IIS, lowered expression of mTOR is not always beneficial. It can be harmful as well. Low expression of mTOR can harm healing and insulin sensitivity. It also can cause cataracts and testicular generation in mouse models2.SirtuinsSirtuins are a family of proteins that act as NAD(+) dependent histone deacetylases 2.  To explain what all of that means, let’s start with histones. Histones are the proteins that DNA wraps around. They serve as a way to compact the DNA (which is very long) in the nucleus especially during cell division. Histones also help control the expression of genes by spatially making some genes more or less available for proteins like RNA polymerase to attach. On histones there are lysines, a type of amino acid. It is on these lysines that histone deacetylases remove acetyl groups, which are small molecules. If all that sounds too confusing, remember this: adding or removing an acetyl groups helps control the expression of genes. In such a manner, Sirtuins help control gene expression.Sirtuins detect when energy levels are low by sensing the coinciding increase of NAD+2.  They also help control catabolic metabolism2. Upregulating some Sirtuins produces anti aging or health promoting effects2.  However, the effect is not strong in all types of Sirtuins for all species, which makes summarizing their effects difficult. For example, in worms, higher expression of SIR2 yields only slight gains in longevity 2.  Overexpression of SIR2’s most similar counterpart in mice, SIRT1, appears to improve health during aging, but not lifespan2.  Another mouse Sirtuin, SIRT6, seems to promote longevity more robustly2. Mice deficient in it experience accelerated aging. Conversely, turning it up results in increased longevity2. There is also SIRT3 which has been shown to help the regeneration ability in old hematopoietic (blood and immune cell producing) cells2 when overexpressed2.AMPKAMP activated kinase ( AMPK) senses AMP (adenosine monophosphate) and ADP (adenosine diphosphate).  These long named molecules are present in higher quantities when nutrients are scarce2.Therefore, it is easiest to remember AMPK as a sensor of fasted or calorie restricted states and catabolism2. Molecularly,  AMPK acts by adding phosphates to serine and threonine3. By doing so, AMPK helps regulate metabolism2. Like sirtuins, higher activity of AMPK has longevity promoting effects2. To illustrate, metformin, a diabetes drug that appears to have a life extension effect, activates AMPK in mice and worms 2. Calorie restriction, which is known to increase lifespan in at least short-lived animals, can also increase the activity of AMPK 3. Conversely, less ampk sensitivity due to cellular stress results in oxidative stress, reduced autophagy,  metabolic syndrome, more fat disposition, and inflammation 3.Conclusion:In summary, there are four key proteins involved in nutrient sensing that might be key contributors in aging. Turning down the pathways of the first two, IGF-1 and mTOR, promote longevity. Both of these are involved in anabolic metabolism (building tissues) and increase in states of nutrient abundance2.  Conversely, turning up the activity of the last two, Sirtuins and AMPK, helps longevity. They work to promote catabolic metabolism (breaking down tissues) and increase with nutrient scarcity2.

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