Why we Age: Deregulated Nutrient Sensing

As described in the Hallmarks of Aging [1], the four pathways of nutrient-sensing regulate metabolism and influence aging. The four associated key protein groups are IGF-1, mTOR, sirtuins, and AMPK. We call these proteins “nutrient-sensing” because nutrient levels influence their activity. Deregulated nutrient sensing is one of the reasons we age.

IGF-1 and the IIS pathway

Insulin-like growth factor (IGF-1) inhibits the secretion of growth hormone by binding to a special receptor on the surface of a cell [2]. 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 [1].

Attenuation of the IGF-1/GH pathway (IIS) appears to improve lifespan in several model organisms [2]. For example, PI3K mice, which have a weakened IIS pathway, live longer. Additionally, FOXO, a transcription factor (a protein that affects the production of RNA), lengthens lifespans in worms and fruit flies by attenuating IIS signaling. In other studies, IGF-1 improves healthspan even when it does not lengthen lifespan [1].

There’s also evidence of harm when IGF-1 activity is high. Higher levels of IGF-1 are associated with increased risk of some types of cancer. This increased cancer risk might be due to IGF’s ability to promote pathways that result in increased cell production [2].

The paradox

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 that the IIS pathway decreases [1].

One explanation for this weirdness is that it’s a last-ditch 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 beneficial. 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 tear [1]. 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 well. On one hand, there is evidence that reduced IGF-1 activity promotes longevity in people with Laron syndrome (who don’t have functional growth hormone receptors), female nonagenarians, and extremely long-lived people. Yet, the epidemiological data is not clear enough to be conclusive on IGF-1’s effects on humans. This is partially due to the difficulty of structuring epidemiological studies on IGF-1, as many external factors, such as nutrition, can confound results [2].

mTOR

Mechanistic target of rapamycin (mTOR) is composed of the mTORC1 and mTORC2 protein complexes. It senses amino acids and is associated with nutrient abundance. It is a kinase, which means it adds phosphates to molecules. mTOR is a champion regulator of anabolic metabolism, the process of building new proteins and tissues. In this way, how it functions is similar to the IIS pathway [1]. 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 as mice, yeast, worms, and flies. Along those lines, mTOR activity increases in the hypothalami of aged mice, which promotes late-life obesity. With rapamycin, an inhibitor of mTOR, these effects are ameliorated. As is the case with, IIS, lowered expression of mTOR is not always beneficial. Low expression of mTOR can harm healing and insulin sensitivity and can cause cataracts and testicular generation in mouse models [1].

Sirtuins

Sirtuins are a family of proteins that act as NAD(+) dependent histone deacetylases [1]. 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 to. 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. In sum, adding or removing acetyl groups helps control the expression of genes, and this is how sirtuins help control gene expression.

Sirtuins detect when energy levels are low by sensing the coinciding increase of NAD+. They also help control catabolic metabolism. Upregulating some sirtuins produces anti-aging or health-promoting effects. However, some sirtuins have only weak effects in some species, which makes summarizing their effects difficult. For example, in worms, higher expression of SIR2 yields only slight gains in longevity. Overexpression of SIR2’s most similar counterpart in mice, SIRT1, appears to improve healthspan but not lifespan [1].

Another mouse sirtuin, SIRT6, seems to promote longevity more robustly. Mice deficient in it experience accelerated aging. Conversely, turning it up results in increased longevity. There is also SIRT3, which has been shown to help the regeneration ability of old hematopoietic (blood and immune cell producing) cells when overexpressed [1].

AMPK

AMP-activated kinase (AMPK) senses AMP (adenosine monophosphate) and ADP (adenosine diphosphate). These molecules are present in higher quantities when nutrients are scarce. Therefore, it is easiest to remember AMPK as a sensor of fasted or calorie-restricted states and catabolism [1]. Molecularly, AMPK acts by adding phosphates to serine and threonine [3]. By doing so, AMPK helps regulate metabolism [1].

Like sirtuins, higher activity of AMPK has longevity-promoting effects. 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. 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 to aging. Turning down the pathways of the first two, IGF-1 and mTOR, promotes longevity. Both of these are involved in anabolic metabolism (building tissues) and an increase in states of nutrient abundance. 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 scarcity [1].

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Milman, S., Huffman, D. M., & Barzilai, N. (2016). The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research. Cell Metabolism, 23(6), 980-989. doi:10.1016/j.cmet.2016.05.014

[3] Salminen, A., & Kaarniranta, K. (2012). AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Research Reviews, 11(2), 230-241. doi:10.1016/j.arr.2011.12.005