Eight genetic modifications for dramatically increasing your chances of living foreverThursday, 17 April, 2008
This is my answer to George Dvorsky’s Eight Tips. His version included boring things like eating good food and getting exercise, which require a lifelong commitment. More my style, however, is just changing my genome so that my cells think I’m living the healthy and calorie-limited lifestyle, whereas I’m actually sitting at my computer all day eating junk food.
1. Decrease your expression of the insulin receptor gene INSR and the insulin-like growth factor receptor gene IGF1R
Instead of eating less and eating healthily, why not just tell your body that you are, but still eat what you want? Mutations of insulin receptors and insulin-like growth factor receptors have been associated with longevity in humans (Suh et al. 2008). Indeed, calorie restriction has been demonstrated to act on insulin and IGF-1 (Breese, Ingram & Sonntag 1991). Mice with one copy of the IGF-1 receptor deleted live 33% longer for females and 13% longer for males (Holzenberger et al. 2003).
Having no insulin receptors is fatal, and a dramatic reduction in this signalling can cause pathologies, like Laron-type dwarfism (sufferers of which incidentally tend to live for a long time). However this could be avoided by targeting this genetic modification to adipose (fat) tissue. FIRKO mice (fat-specific insulin receptor knock-outs) are resistant to diabetes and obesity, and live 20% longer than normal mice (Okamoto & Accili 2003).
Also, the regulatory hormone KLOTHO inhibits both IGF-1 and insulin receptor signals. Overexpression of this gene has been shown to make mice live 20-30% longer (Kurosu et al. 2005). Humans with a mutation at the Klotho gene, KL-VS, have low levels of KLOTHO, and as a result have a much higher risk of stroke, atherosclerosis and osteoporosis (Arking et al. 2005).
2. Increase your expression of PEPCK
The phosphoenolpyruvate carboxykinase (PEPCK) enzyme in involved in energy metabolism (specifically gluconeogenesis), and indeed is one of those enzymes inhibited by insulin (so these effects may not be cumulative with the first modification). Mice expressing 100 times more of this enzyme in their muscles are more active in old age (and, in fact, in their prime), have little body fat and can run twice as fast for up to ten times as long! But, just to put the icing on the cake, they also age more slowly and retain their reproductive capacity into old age (Hakimi, Yang et al. 2007)!
However, mice with more PEPKC do tend to be more aggressive and eat far more, but eating more is not usually a problem for humans and we can probably control our aggression (or, we can fix that with some other modification).
3. Decrease your expression of the apolipoprotein E gene APOE, or switch to the ε2 allele
George advocates supplements like omega fatty acids, but you can regulate your fatty acids by altering your lipid-binding proteins called apolipoproteins. High levels of the apoliprotein epsilon (APOE) have been correlated with arthrosclerosis, neurodegenerative diseases and higher mortality. One particular allele, the ε4 form, is rarer in the very elderly than in the general popular, and another allele, the ε2 form, is more common (Rontu et al. 2006). Studies have confirmed that the ε2 form has a protective effect and that the ε4 form has a negative effect. (Corder et al. 1994).
Similar effects may be present for the other apoproteins, such as apolipoprotein B and C, or cholesteryl ester binding proteins (CETP).
4. Increase your expression of AMPK
Who really wants to go through an exercise routine every day for their entire life? Not me. So, how about just mimicking the benefits of exercise on a cellular level? AMP-activated protein kinase (AMPK) is an enzyme that is expressed in muscle, liver and fat cells in response to exercise (when levels of AMP increase). AMPK is also activated by a drug called metformin (Hawley et al. 2002), which is effective in combating the effects of Type II diabetes and has been shown, in trials on overweight insulin-resistant patients, to reduce risk of diabetes-related death by 42% and all causes mortality by 36% (‘Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)’ 1998).
AMPK also seems to be an inhibitor of the kinase target of Rapamycin (TOR) (Kimura et al. 2003). Inhibition of TOR by RNA interference has been shown to more than double the lifespan of the worm C. elegans (Vellai et al. 2003) and overexpression of the tuberous sclerosis complex genes TSC1 and TSC2 – also TOR inhibitors – can extend the lifespan of Drosophila by 20-30% (Kapahi et al. 2004).
5. Increase your expression of Sirtuin genes, especially SIRT-3
Here’s a genetic modification which could give you some of the benefits of caloric restriction without the dedication and starvation. Increased levels of the Sir2 enzyme can extend lifespan in C. elegans (Tissenbaum & Guarente 2001) and Drosophila (Rogina & Helfand 2004). Mammals don’t have this gene, but they have seven homologues called SIRT1-7. These enzymes are involved in wide areas of energy and metabolism, including insulin signalling, mitochondrial activity and adipocyte function. They have also been shown to regulate the fork-head box-O transcription factors, which been shown to be involved in the process of tumour suppression, but are also involved in ageing (Brunet 2007; Kuningas et al. 2007).
Though SIRT1 has been shown to be involved in caloric restriction in mammals (Cohen et al. 2004), lifespan correlations in humans have been found only with respect to mutations in SIRT-3 (Bellizzi et al. 2005). Regardless, as these enzymes are correlated with insulin signalling, these are possible target for genetic interventions into the ageing process.
6. Increase your oestrogen expression or receptor activity
For point 6, George basically advises to avoid taking life-threatening risks. I can go one better, and suggest you increase your oestrogen expression. It’s no coincidence that most partakers in extreme sports and other risky activities are males – females have more oestrogen, and oestrogen-treated mice have a greater fear response to potentially dangerous situations, but increased activity in calming environs (Morgan & Pfaff 2002).
Plus, in addition to the fact that females tend to live longer than males, there is a lot of evidence that oestrogen affects a lot of age-related genes, such as those involved in repair of oxidative stress (Vina et al. 2008).
Don’t worry guys, once you’re fully grown and still expressing the same levels of testosterone, oestrogen won’t shrink your penis. You ‘might’ grow breasts, but what price immortality, right?
7. Decrease expression of IL6 and other interleukins
Studies have shown that overexpression of the inflammatory cytokines, such as interleukin 6 or 10, are associated with increased mortality (Bonafe et al. 2001; Harris et al. 1999). Indeed, there is an age-related increase in plasma IL-6 level, and those with lower levels of IL-6 are likely to live longer and healthier lives, with less severe bone and neural degeneration (Ershler & Keller 2000; Gallucci et al. 2007). It is known that IL-6 is lessened in calorie-restricted mice , and some studies have found an association between mutations in promoter region of the IL-6 gene and longevity in human populations (Christiansen et al. 2004).
Sex steroids are inhibitors of the interleukins like IL-6, so preventing degeneration of the reproductive system would therefore be a promising target for anti-ageing interventions.
8. Have more copies of the Arf/p53 genes
So, if you’ve done the above you’re now a safe person with resistance to cardiovascular disorders and neurodegenerative diseases, but cancer is a leading cause of death among the elderly, so you’ll have to prevent that? Some people have thought that the same mechanism used to destroy cancer cells would also destroy aged cells, leading to degeneration with ageing. But maybe not. Super-Arf/super-p53 (Genetically engineered mice with an extra copy of both Arf and p53) live 16% longer and show less physiological decay with ageing, such as greater motor control and hair regeneration in old age (Matheu et al. 2007).
p53, and its regulator Arf, are integral to stress-responses, and have been shown to cause the expression of antioxidants in response to mild stress (Sablina et al. 2005) and to shut down severely damaged cells by apoptosis (cell suicide). They are also common genes to be mutated in cancer cells, so an extra copies provides a backup for the cell as well as increasing their activity. Provided the regulation is not disturbed (as some other overexpression studies may have done), an extra copy of p53 should increase resistance to cancer and reduce the accumulation of aged/damaged cells. It isn’t known yet whether the longevity is due to increased cancer resistance or to actually preventing the ageing process, but from where I stand, it’s all good.
By the way, you may be wondering what happened to the mention of the telomerase enzyme. Well, it’s not true that organisms with longer telomeres live much longer (humans have very short telomeres, but live longer than any other mammal) and it seems that increasing it in mammals is more likely to cause a tumour than provide the elixir of life. So, although it is likely to be a solution in the long-term, I can’t see it being a good idea until we can cure cancer. (UPDATE: It appears this is exactly what some researchers have done: see my blog post on that research)
References can be accessed by hitting the ‘read the rest of this entry’ link below.
- Arking, DE, Atzmon, G, Arking, A, Barzilai, N & Dietz, HC 2005, ‘Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity’, Circulation Research, vol. 96, no. 4, pp. 412-8.
- Bellizzi, D, Rose, G, Cavalcante, P, Covello, G, Dato, S, De Rango, F, Greco, V, Maggiolini, M, Feraco, E, Mari, V, Franceschi, C, Passarino, G & De Benedictis, G 2005, ‘A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages’, Genomics, vol. 85, no. 2, pp. 258-63.
- Bonafe, M, Olivieri, F, Cavallone, L, Giovagnetti, S, Marchegiani, F, Cardelli, M, Pieri, C, Marra, M, Antonicelli, R, Lisa, R, Rizzo, MR, Paolisso, G, Monti, D & Franceschi, C 2001, ‘A gender-dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity’, European Journal of Immunology, vol. 31, no. 8, pp. 2357-61.
- Breese, CR, Ingram, RL & Sonntag, WE 1991, ‘Influence Of Age And Long-Term Dietary Restriction On Plasma Insulin-Like Growth Factor-I (IGF-1), IGF-1 Gene-Expression, And IGF-1 Binding-Proteins’, Journals of Gerontology, vol. 46, no. 5, pp. B180-B7.
- Brunet, A 2007, ‘Aging and cancer: killing two birds with one worm’, Nature Genetics, vol. 39, no. 11, pp. 1306-7.
- Christiansen, L, Bathum, L, Andersen-Ranberg, K, Jeune, B & Christensen, K 2004, ‘Modest implication of interleukin-6 promoter polymorphisms in longevity’, Mechanisms of Ageing and Development, vol. 125, no. 5, pp. 391-5.
- Cohen, HY, Miller, C, Bitterman, KJ, Wall, NR, Hekking, B, Kessler, B, Howitz, KT, Gorospe, M, de Cabo, R & Sinclair, DA 2004, ‘Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase’, Science, vol. 305, no. 5682, pp. 390-2.
- Corder, EH, Saunders, AM, Risch, NJ, Strittmatter, WJ, Schmechel, DE, Gaskell, PC, Rimmler, JB, Locke, PA, Conneally, PM, Schmader, KE, Small, GW, Roses, AD, Haines, JL & Pericak-Vance, MA 1994, ‘Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease’, Nature Genetics, vol. 7, no. 2, pp. 180-4.
- ‘Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)’, 1998, The Lancet, vol. 352, no. 9131, pp. 854-65.
- Ershler, WB & Keller, ET 2000, ‘Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty’, Annual Review of Medicine, vol. 51, pp. 245-70.
- Gallucci, M, Amici, GP, Ongaro, F, Gajo, GB, De Angeli, S, Forloni, GL, Albani, D, Prato, F, Polito, L, Zanardo, A & Regini, C 2007, ‘Associations of the plasma interleukin 6 (IL-6) levels with disability and mortality in the elderly in the Treviso Longeva (Trelong) study’, Archives of Gerontology and Geriatrics, vol. 44, no. Supplement 1, pp. 193-8.
- Hakimi, P, Yang, J, Casadesus, G, Massillon, D, Tolentino-Silva, F, Nye, CK, Cabrera, ME, Hagen, DR, Utter, CB, Baghdy, Y, Johnson, DH, Wilson, DL, Kirwan, JP, Kalhan, SC & Hanson, RW 2007, ‘Overexpression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle Repatterns Energy Metabolism in the Mouse’, Journal of Biological Chemistry, vol. 282, no. 45, pp. 32844-55.
- Harris, TB, Ferrucci, L, Tracy, RP, Corti, MC, Wacholder, S, EttingerJr, WH, Heimovitz, H, Cohen, HJ & Wallace, R 1999, ‘Associations of elevated Interleukin-6 and C-Reactive protein levels with mortality in the elderly’, The American Journal of Medicine, vol. 106, no. 5, pp. 506-12.
- Hawley, SA, Gadalla, AE, Olsen, GS & Hardie, DG 2002, ‘The Antidiabetic Drug Metformin Activates the AMP-Activated Protein Kinase Cascade via an Adenine Nucleotide-Independent Mechanism’, Diabetes, vol. 51, no. 8, pp. 2420-5.
- Holzenberger, M, Dupont, J, Ducos, B, Leneuve, P, Geloen, A, Even, PC, Cervera, P & Le Bouc, Y 2003, ‘IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice’, Nature, vol. 421, no. 6919, pp. 182-7.
- Jasnow, AM, Mong, JA, Romeo, RD & Pfaff, DW 2007, ‘Estrogenic regulation of gene and protein expression within the amygdala of female mice’, Endocrine, vol. 32, no. 3, pp. 271-9.
- Kapahi, P, Zid, BM, Harper, T, Koslover, D, Sapin, V & Benzer, S 2004, ‘Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway’, Current Biology, vol. 14, no. 10, pp. 885-90.
- Kimura, N, Tokunaga, C, Dalal, S, Richardson, C, Yoshino, K-i, Hara, K, Kemp, BE, Witters, LA, Mimura, O & Yonezawa, K 2003, ‘A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway’, Genes to Cells, vol. 8, no. 1, pp. 65-79.
- Kuningas, M, Magi, R, Westendorp, RGJ, Slagboom, PE, Remm, M & van Heemst, D 2007, ‘Haplotypes in the human Foxo1a and Foxo3a genes; impact on disease and mortality at old age’, European Journal of Human Genetics, vol. 15, no. 3, pp. 294-301.
- Kurosu, H, Yamamoto, M, Clark, JD, Pastor, JV, Nandi, A, Gurnani, P, McGuinness, OP, Chikuda, H, Yamaguchi, M, Kawaguchi, H, Shimomura, I, Takayama, Y, Herz, J, Kahn, CR, Rosenblatt, KP & Kuro-o, M 2005, ‘Suppression of aging in mice by the hormone Klotho’, Science, vol. 309, no. 5742, pp. 1829-33.
- Matheu, A, Maraver, A, Klatt, P, Flores, I, Garcia-Cao, I, Borras, C, Flores, JM, Vina, J, Blasco, MA & Serrano, M 2007, ‘Delayed ageing through damage protection by the Arf/p53 pathway’, Nature, vol. 448, no. 7151, pp. 375-9.
- Morgan, MA & Pfaff, DW 2002, ‘Estrogen’s effects on activity, anxiety, and fear in two mouse strains’, Behavioural Brain Research, vol. 132, no. 1, pp. 85-93.
- Okamoto, H & Accili, D 2003, ‘In vivo mutagenesis of the insulin receptor’, Journal of Biological Chemistry, vol. 278, no. 31, pp. 28359-62.
- Rogina, B & Helfand, SL 2004, ‘Sir2 mediates longevity in the fly through a pathway related to calorie restriction’, PProceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 45, pp. 15998-6003.
- Rontu, R, Ojala, P, Hervonen, A, Goebeler, S, Karhunen, PJ, Nikkila, M, Kunnas, T, Jylha, M, Eklund, C, Hurme, M & Lehtimaki, T 2006, ‘Apolipoprotein E genotype is related to plasma levels of C-reactive protein and lipids and to longevity in nonagenarians’, Clinical Endocrinology, vol. 64, no. 3, pp. 265-70.
- Sablina, AA, Budanov, AV, Ilyinskaya, GV, Agapova, LS, Kravchenko, JE & Chumakov, PM 2005, ‘The antioxidant function of the p53 tumor suppressor’, Nature Medicine, vol. 11, no. 12, pp. 1306-13.
- Suh, Y, Atzmon, G, Cho, MO, Hwang, D, Liu, B, Leahy, DJ, Barzilai, I & Cohen, P 2008, ‘Functionally significant insulin-like growth factor I receptor mutations in centenarians’, Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 9, pp. 3438-42.
- Tissenbaum, HA & Guarente, L 2001, ‘Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans’, Nature, vol. 410, no. 6825, pp. 227-30.
- Vellai, T, Takacs-Vellai, K, Zhang, Y, Kovacs, AL, Orosz, L & Muller, F 2003, ‘Genetics – Influence of TOR kinase on lifespan in C-elegans’, Nature, vol. 426, no. 6967, pp. 620-.
- Vina, J, Sastre, J, Pallardo, FV, Gambini, J & Borras, C 2008, ‘Modulation of longevity-associated genes by estrogens or phytoestrogens’, Biological Chemistry, vol. 389, no. 3, pp. 273-7.