Which Genes Are Connected to Longevity?

Mapping of the human genome, or the human genome project, resulted in us having access to the database that contains all human genes on a list. The project, which took 13 years to finish, opened up so many possibilities for targeted personal medicine (1). It also unraveled an entirety of genes involved in basic human functions, diseases and physiological processes.

One of these processes is aging, which is characterized by lower energy levels, decreasing physical activity and more risk for developing different diseases (2). All of this happens through a cascade of individual reactions within our cells that result in changes each time our cells multiply. Eventually, cells start to lose their abilities to perform certain functions, and our bodies manifest it as aging. Several scientific methods, along with the genome project, allow us to pinpoint what in the cell starts “aging” and how we can possibly target it. As with everything in the cells, we know the start is found within our DNA, meaning our genes.

Methods used to determine the human genome also allowed scientists to continue the work on individuals years after. Today, we can analyze the amounts of certain genes we have, and compare those in states of health or disease. We can also compare them between different cultural and geographical groups, as well as ages. Younger individuals have a different amount of some genes than older ones.

This is exactly how several genes, connected to longevity, were discovered. Many family studies showed that longevity can be inherited through generations to up about 40% (3). The other 60% account for environmental and lifestyle factors, but 40% is still a significant amount. This led to a discovery of several genes and their products which are connected to some individuals possibly living longer than others (2).

Some of these genes are connected to the cell multiplication process itself, and some are more related to damage control that cells perform under stress. Here is a list of all of them:

FOXO

One of the most known and recognizable genes/enzymes associated with aging is FOXO, which stands for “Forkhead box 0”. It is a product of the daf16 gene, and it functions as a transcriptional factor (4). Transcription is a process in which the DNA letters get transcribed into mRNA letters, eventually resulting in a protein. The role of transcriptional factors is to “sit” on top of certain parts of DNA and get certain genes to be transcribed (expressed). FOXO is not the only transcriptional factor in the cell, but it is involved in regulating many cell processes through its role, such as:

• insulin and insulin growth factor signaling,
• resistance to oxidative stress and damage,
• apoptosis or programmed cell death,
• stem cell development,
• immunity,
• metabolism.

The involvement of FOXO in aging and longevity has already been studied in animal models, such as in the polyp Hydra vulgaris, the worm Caenorhabditis elegans, and the fruit fly Drosophila melanogaster. Those studies showed great potential of FOXO being involved in aging, where decreased amounts of FOXO were found in older subjects.

However, in mammals like mice and humans, the story is a bit more complicated. Mammals have 4 different isoforms of FOXO expressed, FOXO1, 3, 4, and 6, all expressed in different tissues, with slightly different functions, not completely known yet. Studies performed on mice show FOXO to be very important in indirect regulation of muscle degradation (5), autophagy (6), and the development of Parkinson’s disease (7), and in most cases it was the FOXO3 isoform. Given the genetic similarity between mice and humans, this elucidated great clinical interest for FOXO (and specifically FOXO3 (8)) in humans, which will soon result in many clinical human studies that reveal FOXO as a potential therapeutic and anti-aging target.

p53

Mentioning cell replication and stability cannot go without mentioning p53, or the tumor suppressing protein 53. Encoded by the gene carrying the same name, p53 regulates different phases of cell multiplication, controls genome stability, and ultimately suppresses the development of cancer, by stopping uncontrolled and rapid cell division. Also, another function of p53 is to prevent DNA damage, which is one of the causes of genome instability, cell death, and which ultimately determines cell’s lifespan (9). 

With these functions it seems plausible p53 would be very much involved in longevity, and indeed it is. A myriad of studies has shown p53 is involved in longevity in model organisms like mice, fruit flies, worms, but also in humans. In all mammals, p53 controls the appropriate amount of cell division for the body to regenerate, but to also prevent too much division that would result in the development of cancer (10). It seems the biggest role p53 has in aging and longevity is the suppression of tumor development from early age and throughout the whole life. 

Sirtuins (SIRTs)

Sirtuins are a family of proteins that are indirectly connected to the regulation of gene expression, genome integrity, cell cycle, cell metabolism, and gene silencing. Sirtuins function with the help of NAD+ or nicotinamide adenine dinucleotide, and are affected by the amount of this molecule in the cell (11). 

As an example of their indirect regulation of cell longevity, sirtuins regulate the expression of FOXO proteins, as well as p53 (12). Enhanced levels of sirtuins have been linked to a longer lifespan in almost all model organisms, like mice, fruit flies, yeast and worms. It was shown that the lives of female mice were prolonged up to 16% after the overexpression of the brain-specific SIRT1 (13). 

Clinical studies done on human test subjects are to be done, but sirtuins exhibit a lot of potential, especially because they could be targeted with the molecule they depend on, NAD+. Unfortunately, NAD+ cannot be taken up by the body through supplementation, but its precursor, NMN or nicotinamide mononucleotide, can be. Studies have already shown that the external supplementation of NMN reduces DNA damage, fat accumulation, heart failure, and telomere length in mice, all through the SIRT pathway (14, 15).

Apolipoprotein E (APOE)

APOE gene encodes for the apolipoprotein E (APOE) protein, which binds to fat molecules (lipids) and transports them throughout our body. Other than that, APOE regulates blood glucose levels, cardiovascular health, and brain cell homeostasis (16). There are also different possible isoforms of APOE a human can have: APOE2, 3, and 4. Approximately 50% of the world's population has the APOE3 isoform. 

Unlike some of the other genes named in this article, APOE has provenly been connected to longevity in human studies already. The conclusions of these studies were:

• APOE contributes up to 3.5% in the overall process of aging (17),
• APOE4 has been linked to the onset of Alzheimer's disease and cognitive decline (18, 19), 
• Subjects having the APOE4 isoform live cca. 4.2 years shorter than others having different isoforms (20),
• Having APOE2 favors longevity in comparison to APOE4, as proven in Japanese individuals (21). 

Even though we know a lot about APOE already, the development of APOE targeted therapies is still under construction. This is mainly because APOE is involved in so many processes that we first have to understand how changing the amounts of active APOE would affect every single one of them and what would the main consequences be.

How can I check the expression of my own genes?

One of the most interesting and beneficial things you can do for yourself is to check what the status of your genome is. It is much easier said than done, but luckily, it became so popular in the past decade, you won’t have to go too far to find a laboratory that does it. 

What can sequencing your genome do for you? It will reveal whether you have mutations in some of your genes that could potentially be dangerous for your health. Mutations alter the behavior of a gene, making all the processes they perform slightly different, which can have adverse effects on your well-being. Genes that control tumor suppression, like p53, will be looked at the most. It can also show if you have a predisposition to develop a disease other than cancer, such as Alzheimer’s or Huntington’s. 

The test itself cannot change the status of your genes, but it can make you aware of all the possibilities you can do to prolong your life, because many diseases have an environmental component in their development as well. 

Literature:

1. Collins FS, McKusick VA. Implications of the Human Genome Project for Medical Science. JAMA. 2001;285(5):540–544. doi:10.1001/jama.285.5.540.
2. Bin-Jumah MN, Nadeem MS, Gilani SJ, Al-Abbasi FA, Ullah I, Alzarea SI, Ghoneim MM, Alshehri S, Uddin A, Murtaza BN, Kazmi I. Genes and Longevity of Lifespan. Int. J. Mol. Sci. 23:1499. doi: 10.3390/ijms23031499. 
3. Sebastiani P, Solovieff N, Dewan AT, Walsh KM, Puca A, Hartley SW, Melista E, Andersen S, Dworkis DA, Wilk JB, Myers RH, Steinberg MH, Montano M, Baldwin CT, Hoh J, Perls TT. Genetic signatures of exceptional longevity in humans. PLoS One. 7:e29848. doi: 10.1371/journal.pone.0029848. 
4. Martins R, Lithgow GJ, Link W. Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell. 15:196-207. doi: 10.1111/acel.12427. 
5. Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ (2004) The IGF‐1/PI3K/Akt pathway prevents expression of muscle atrophy‐induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol. Cell 14, 395–403. doi: 10.1016/s1097-2765(04)00211-4.
6. Warr MR, Binnewies M, Flach J, Reynaud D, Garg T, Malhotra R, Debnath J, Passegue E (2013) FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327. doi: 10.1038/nature11895.
7. Kume S, Uzu T, Horiike K, Chin‐Kanasaki M, Isshiki K, Araki S, Sugimoto T, Haneda M, Kashiwagi A, Koya D (2010) Calorie restriction enhances cell adaptation to hypoxia through Sirt1‐dependent mitochondrial autophagy in mouse aged kidney. J. Clin. Invest. 120, 1043–1055. doi: 10.1172/JCI41376.
8. Sanese P, Forte G, Disciglio V, Grossi V, Simone C. FOXO3 on the Road to Longevity: Lessons From SNPs and Chromatin Hubs. Comput Struct Biotechnol J. 17:737-745. doi: 10.1016/j.csbj.2019.06.011. 
9. Boyd-Kirkup J.D., Green C.D., Wu G., Wang D., Han J.D. Epigenomics and the regulation of aging. Epigenomics. 5:205–227. doi: 10.2217/epi.13.5.
10. Maier B., Gluba W., Bernier B., Turner T., Mohammad K., Guise T., Sutherland A., Thorner M., Scrable H. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18:306–319. doi: 10.1101/gad.1162404.
11. Yoshizaki T., Schenk S., Imamura T., Babendure J.L., Sonoda N., Bae E.J., Oh D.Y., Lu M., Milne J.C., Westphal C., et al. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am. J. Physiol. Metab. 298:E419–E428. doi: 10.1152/ajpendo.00417.2009.
12. Bernier M., Paul R.K., Martin-Montalvo A., Scheibye-Knudsen M., Song S., He H.-J., Armour S.M., Hubbard B., Bohr V.A., Wang L., et al. Negative Regulation of STAT3 Protein-mediated Cellular Respiration by SIRT1 Protein. J. Biol. Chem. 286:19270–19279. doi: 10.1074/jbc.M110.200311.
13. Satoh A., Brace C.S., Rensing N., Cliften P., Wozniak D.F., Herzog E., Yamada K.A., Imai S.-I. Sirt1 Extends Life Span and Delays Aging in Mice through the Regulation of Nk2 Homeobox 1 in the DMH and LH. Cell Metab. 18:416–430. doi: 10.1016/j.cmet.2013.07.013.
14. Mills K.F., Yoshida S., Stein L.R., Grozio A., Kubota S., Sasaki Y., Redpath P., Migaud M.E., Apte R.S., Uchida K., et al. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 24:795–806. doi: 10.1016/j.cmet.2016.09.013.
15. Amano H., Chaudhury A., Rodriguez-Aguayo C., Lu L., Akhanov V., Catic A., Popov Y.V., Verdin E., Johnson H., Stossi F., et al. Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease. Cell Metab. 29:1274–1290.e9. doi: 10.1016/j.cmet.2019.03.001.
16. Mahley RW, Rall SC Jr. Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 2000;1:507-37. doi: 10.1146/annurev.genom.1.1.507.
17.  Ewbank DC. The APOE gene and differences in life expectancy in Europe. J Gerontol. A. Biol. Sci. Med. Sci. 59(1):16-20. doi: 10.1093/gerona/59.1.b16.  
18. Song Y., Stampfer M.J., Liu S. Meta-Analysis: Apolipoprotein E Genotypes and Risk for Coronary Heart Disease. Ann. Intern. Med. 2004;141:137–147. doi: 10.7326/0003-4819-141-2-200407200-00013.
19. Fullerton SM, Clark AG, Weiss KM, Nickerson DA, Taylor SL, Stengârd JH, Salomaa V, Vartiainen E, Perola M, Boerwinkle E, Sing CF. Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism. Am. J. Hum. Genet. 67(4):881-900. doi: 10.1086/303070.
20. Kulminski AM, Arbeev KG, Culminskaya I, Arbeeva L, Ukraintseva SV, Stallard E, Christensen K, Schupf N, Province MA, Yashin AI. Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan. PLoS Genet. 10:e1004141. doi: 10.1371/journal.pgen.1004141.
21. Garatachea N, Emanuele E, Calero M, Fuku N, Arai Y, Abe Y, Murakami H, Miyachi M, Yvert T, Verde Z, Zea MA, Venturini L, Santiago C, Santos-Lozano A, Rodríguez-Romo G, Ricevuti G, Hirose N, Rábano A, Lucia A. ApoE gene and exceptional longevity: Insights from three independent cohorts. Exp. Gerontol. 53:16-23. doi: 10.1016/j.exger.2014.02.004.