How does insulin affect your lifespan?

The question of longevity, or extending human lifespan, is a difficult one to answer. There are multiple factors that influence aging, through different molecular pathways and metabolisms. One of the molecules that influences aging for sure is insulin, and the insulin signaling pathway is one that provides a lot of insight into how metabolism connects to having a longer lifespan.

In this article, we will explore the role of insulin in aging, and discuss the available scientific research. If you're interested in other longevity pathways, read our articles:

• The Role of Autophagy in Health and Longevity
• Are AMPK and mTOR pathways the molecular key to longevity?

What is insulin?

Insulin is a hormone produced in the pancreas, as a response to an increase in blood sugar (glucose) levels. This primarily happens after we eat. The released insulin circulates in the blood and binds itself to our cells, telling them they should take up glucose. Once they take up glucose, the levels of sugar in blood are going to decrease. 

Insulin is probably one of the most known molecules out there, since the disruption of insulin production leads to the development of type II diabetes. Somebody who inherently doesn't produce insulin suffers from type I diabetes. In both cases, diabetics need to take insulin in order to signal their cells to take up blood glucose, as high blood sugar levels can be deadly. 

When insulin binds to the cells' surfaces, that reaction is only a trigger to a series of complex biochemical events that result in cells taking up sugar. That entire process is named the insulin/IGF-1 pathway. 

The insulin/IGF-1 pathway

After insulin has successfully bound itself to the correct receptors on the cells, a whole cascade of events is going to happen. It includes (1, 2):

• Binding of insulin to its receptor activates the receptor.
• The activated insulin receptor will activate insulin receptor substrates, which then activate the protein phosphoinositide 3-kinase (PI3K).
• PI3K activates the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which in turn activates the protein kinase B (PKB/Akt), which signals to the glucose transporters that they should go to the cell membrane and take in glucose.
• Activation of Akt also influences many other reactions involved in metabolism and cell growth.

The other part of this pathway entails the insulin growth factor 1 (IGF-1), which is a growth hormone produced by the liver. IGF-1 travels through the blood similarly to insulin, and binds itself to cells, again, similarly to insulin. Even the cell receptors for IGF-1 are very similar to insulin receptors. 

This leads to some consequences, for example then both insulin and IGF-1 activate the PI3K/Akt pathway. However, insulin is primarily involved in the regulation of glucose metabolism, and IGF-1 stimulates cell proliferation and differentiation, and it plays a critical role in muscle growth and repair.

The insulin/IGF-1 pathway and longevity

The insulin signaling pathway also plays a significant role in the regulation of aging and longevity. Research on various organisms, like flies, mice, and humans, has shown that reduced insulin signaling extends lifespan.

Mechanisms Linking Insulin Signaling to Longevity

There are different ways and mechanisms in which insulin and IGF-1 influence aging, and be manipulated to prolong the lifespan. These are:

• Stress reduction: A decrease in insulin/IGF-1 leads to better stress resistance, which is mediated by certain proteins named FOXO in humans.
• Less insulin leads to more repair: if there is less insulin/IGF-1, the metabolism is going to switch from producing energy and growing, to maintenance and repair, which includes increased autophagy. This process is increased by prolonged fasting. 
• Reduced inflammation: Lower amounts of insulin/IGF-1 have been linked with less inflammation, and we know a lot of inflammation leads to a lot of problems, and faster aging. Less inflammation can also prevent the development of many age-related diseases.

Scientific research on insulin and longevity

There is a decent amount of research out there which connects insulin/IGF-1 to longevity, in one way or another. However, there is a certain consensus on the matter, and that is that less insulin/IGF-1 leads to a prolonged lifespan. Unfortunately, there is not much scientific research out there on humans, but even early research confirms what we know from animal studies.

Some of the most impressive research on insulin and longevity came from laboratory worms. When scientists mutated the insulin pathway and reduced its activity, the worm's lifespan significantly increased, and those worms lived twice as long as the "normal" ones (3). Similar has been shown in fruit flies and mice (4, 5). 

When it comes to human studies, we have several insights:

• Some studies showed that people of smaller size in different regions of the world on average live longer. However, this might not be due to a decrease in metabolic rate, as one Chinese study found the correlation only for men, but not for women (6, 7). 
• Genotyping studies, which look into our genes, looked into the genetic profiles of many long-lived people. They found that genetic components of the insulin/IGF-1 pathway, like the protein FOXO we mentioned earlier, are crucial determining factors in human longevity. Not only FOXO, but other proteins of the insulin/IGF-1 signaling pathway are important for a longer lifespan, like Akt and PIK3 (8, 9, 10). 

Conclusion

In conclusion, the insulin/IGF-1 signaling pathway plays crucial roles in regulating metabolism, growth, and aging. Research tells us that reduced signaling through this pathway is associated with increased lifespan in many organisms.

Less activation of these pathways means less stress and inflammation. Can we modulate this pathway for our benefit and longevity? Yes, we can, by restricting our caloric intake, and by fasting that induces autophagy. Don't overconsume food and caloric beverages, as this might lead to cardiovascular and metabolic disorders like diabetes and obesity anyway. Everything should be done in moderation, and after consulting with a healthcare professional. 

Read more on caloric restriction and autophagy here:

• Can Caloric Restriction Mimetics Fight Aging and Obesity at the Same Time?
• The Role of Autophagy in Health and Longevity.

Literature sources:

1. De Meyts P. The Insulin Receptor and Its Signal Transduction Network. [Updated 2016 Apr 27]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK378978/
2. Hakuno F, Takahashi SI. IGF1 receptor signaling pathways. J Mol Endocrinol. 2018 Jul;61(1):T69-T86. doi: 10.1530/JME-17-0311.
3. Li WJ, Wang CW, Tao L, Yan YH, Zhang MJ, Liu ZX, Li YX, Zhao HQ, Li XM, He XD, Xue Y, Dong MQ. Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans. Nat Commun. 2021 Jul 27;12(1):4568. doi: 10.1038/s41467-021-24816-z.
4. Partridge L, Alic N, Bjedov I, Piper MD. Ageing in Drosophila: the role of the insulin/Igf and TOR signalling network. Exp Gerontol. 2011 May;46(5):376-81. doi: 10.1016/j.exger.2010.09.003.
5. Shimizu T, Baba T, Ogawara M, Shirasawa T. Lifespan and glucose metabolism in insulin receptor mutant mice. J Aging Res. 2011;2011:315640. doi: 10.4061/2011/315640.
6. Han F, Hu F, Wang T, Zhou W, Zhu L, Huang X, Bao H, Cheng X. Association Between Basal Metabolic Rate and All-Cause Mortality in a Prospective Cohort of Southern Chinese Adults. Front Physiol. 2022 Jan 4;12:790347. doi: 10.3389/fphys.2021.790347.
7. Samaras TT. Should we be concerned over increasing body height and weight? Exp Gerontol. 2009 Jan-Feb;44(1-2):83-92. doi: 10.1016/j.exger.2008.02.002.
8. Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD. FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13987-92. doi: 10.1073/pnas.0801030105.
9. Zhao Y, Liu YS. Longevity Factor FOXO3: A Key Regulator in Aging-Related Vascular Diseases. Front Cardiovasc Med. 2021 Dec 23;8:778674. doi: 10.3389/fcvm.2021.778674.
10. Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J, Joyner AH, Schork NJ, Hsueh WC, Reiner AP, Psaty BM, Atzmon G, Barzilai N, Cummings SR, Browner WS, Kwok PY, Ziv E; Study of Osteoporotic Fractures. Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell. 2009 Aug;8(4):460-72. doi: 10.1111/j.1474-9726.2009.00493.x.