Twenty-four years ago the field of aging research was galvanized when it was discovered that modification of a single gene could more than double the maximum life span of nematode worms.1 Since that time genetic manipulations have been used to increase the life span of many species, including the creation of Ames dwarf mice, which live nearly 50% longer than their genetically normal siblings.2 Many researchers hope that similar results can be achieved for humans.
That longevity is controlled by genetics seems obvious from the facts that mice age to death in a few years, cats in less than two decades, and humans live much longer. Some scientists think aging is entirely due to control over production and repair of damaging agents from metabolism, others think genes produce substances that induce aging, while still other researchers believe aging results from a decline in gene control.
For the last decade, Cold Spring Harbor Laboratory on Long Island, New York, has been holding “Molecular Genetics of Aging” conferences every two years. The most recent such meeting featured more than 100 eight-minute presentations and about 80 posters by most of the world’s leading scientists in the field of the genetics of aging. Scientific conferences often include poster sessions in which scientists who do not present their work in front of an audience can present their work in the form of a poster that can be viewed and discussed with other scientists. Poster sessions allow for much more personal interaction between the scientists.
Among the key candidates as regulators of aging has been a family of enzymes known as sirtuins. Sirtuin was first discovered to extend life span in yeast3 and later discovered to extend the life span of nematode worms and fruit flies.4 Deleting sirtuins prevents the life span-increasing benefits of calorie restriction in many species.5 Resveratrol, a chemical found in the skin of red grapes that stimulates sirtuin activity, has been shown to increase the life span of worms and flies.6 Resveratrol has also extended the life span of mice fed a high-fat diet.7 Complicating the question of how sirtuins affect aging is the fact that mammals have at least seven different sirtuins, designated SIRT1 - SIRT7.8 SIRT1 is the mammalian analog of the sirtuin found in yeast, worms, and flies. Resveratrol activates SIRT1, but not the other sirtuins.
At the conference Haim Cohen, PhD, Bar-Ilan University, Faculty of Life Sciences, Israel, reported on his work comparing the effects of SIRT1 and SIRT6. Mice induced to make extra amounts of SIRT6 showed similar protection against the damaging effects of a high fat diet as mice that have been fed resveratrol, despite the fact that resveratrol stimulates SIRT1 but not SIRT6.7,9 SIRT6 promotes insulin signaling and protects against the metabolic diseases often associated with obesity and aging. Cohn noted that SIRT6 levels become lower in obese humans. In his more recent research, Cohen showed that male (but not female) mice over-expressing SIRT6 live 10-15% longer than normal mice.10 It had been discovered many years earlier that mice engineered to produce no SIRT6 will age prematurely.11 In trying to understand why SIRT6 extends male but not female mouse life span, scientists have referred to the higher cancer incidence normally seen in male mice and the higher serum IGF-1 hormone in males.12
Vera Gorbunova, PhD , Professor, University of Rochester Department of Biology, New York, reported on her research on SIRT1 and SIRT6 using human cell cultures. Cells contain special enzymes that repair various kinds of breaks in DNA strands. Dr. Gorbunova found that SIRT1 had no effect on repair of double-strand breaks, but increasing SIRT6 could more than triple both mechanisms for repair of double-strand DNA breaks.13 Her more recent research has shown that the benefits of SIRT6 on DNA repair are due to the ability of SIRT6 to recruit various DNA repair proteins to the site of DNA damage.14 Because DNA damage leads to cancer and other maladies of aging, finding molecules that stimulate SIRT6 just as resveratrol stimulates SIRT1 has the potential to extend human life span and healthspan.
Yelena Budovskaya, PhD , Assistant Professor, University of Amsterdam, Swammerdam Institute for Life Sciences, Netherlands, holds the view that aging is not the result of accumulated damage, but rather is the result of “developmental pathways that go awry late in life.”15 Her study of nematode worms supports her view. Wnt is a protein found in all multi-cellular organisms that is essential for growth and development. In a yet-to-be-published study, Budovskaya found that on the fifth day of worm adulthood, the level of Wnt is 5 times greater than on the first day of adulthood, and on the tenth day of adulthood it is 10 times greater. By inactivating Wnt function on the first day of adulthood, she was able to extend the life span of her nematode worms by 40-50%. Inactivation later than the first day of adulthood was less beneficial. In mammals, Wnt protein increases with age, and this increase causes muscle stem cells to age.16 So there is a potential for a Wnt-blocking molecule to delay aging in adult humans.
Telomeres are structures that protect the end of chromosomes, much like the caps on shoelaces protect shoelaces from becoming frayed. Many aging researchers believe that telomere length is a critical determinant of aging, because cells stop dividing when telomeres become too short. Short telomeres in humans are associated with diseases of aging and reduced longevity. Mice have often been used as model mammals for many aspects of aging research, including research on telomeres.17 But mice, with their long telomeres, short life spans, and high levels of telomerase (an enzyme that lengthens telomeres) might be a poor model for studying the effects of telomere length on human aging. Catarina Henriques, PhD, Instituto Gulbenkian de Ciencia, Telomeres and Genome Stability Lab, Portugal, has found that telomere length in zebrafish is comparable to that in humans, and that zebrafish with experimentally reduced telomerase showed symptoms of premature aging. Dr. Henriques believes that, with their four-year life span and telomere behavior more similar to humans than mice, zebrafish would be a more relevant human model than mice for studying the relationship between telomeres and aging.
In separate presentations, both Darren Baker, PhD, Assistant Professor, Mayo Clinic College of Medicine, Department of Biochemistry and Molecular Biology, Rochester, Minnesota, and his supervisor (Jan van Deursen) discussed Baker’s research results. Dr. Baker has been studying mutant mice that contain low levels of a protein called BubR1, which is necessary for cell division. BubR1 protein normally declines with age. Baker showed that graded reductions of BubR1 in his mutant mice resulted in increasing signs of aging and chromosomal abnormalities associated with cancer. 18 His mutant mice also displayed endothelial dysfunction similar to the blood vessels of aging humans.19 Many of the cells in Baker’s mutant mice became prematurely senescent (non-dividing). He found the proteins that caused this change.20 His tour de force was in 2011, when he demonstrated that using the protein marker he discovered to eliminate senescent cells in mice resulted in rejuvenating effects in the mice.21 Needless to say, there is hope that similar procedures can be applied to humans.
During her eight-minute presentation, Nirinjini Naidoo, PhD, University of Pennsylvania Perelman School of Medicine, Division of Sleep Medicine, summarized the studies and reviews she has published on the subject of endoplasmic reticulum stress (ER stress), sleep deprivation, and aging. The endoplasmic reticulum is the area of cells where proteins are folded into a conformation that will allow those proteins to function properly. ER stress occurs when too many proteins have been incorrectly folded in the endoplasmic reticulum. A cell can often correct ER stress by reducing the rate of protein production, increasing the number of protein-folding molecules, or by increasing protein degradation. These corrective responses become increasingly defective with aging. Unresolved ER stress leads to cell death (apoptosis). Dr. Naidoo has shown a 30% reduction in a protein-folding molecule in the cerebral cortex of old mice compared to young mice.22 Many key ER molecules become increasingly oxidized with age.23
Naidoo said that both sleep and wakefulness become increasingly fragmented with age. Another study by Dr. Naidoo demonstrated ER stress in the mouse cerebral cortex with 6 hours of sleep deprivation.24 Although she can experimentally induce ER stress with sleep deprivation, Naidoo said she has still not determined the exact mechanism by which this occurs. Protein misfolding is a key process in many age-related neurodegenerative diseases, including Alzheimer’s Disease, Huntington’s Disease, and Parkinson’s Disease.25 Accumulated cholesterol in the endoplasmic reticulum caused ER stress in macrophages and is a key factor in atherosclerosis.26 ER stress is a central feature of insulin resistance with type II diabetes.27,28 Reducing ER stress by getting more sleep may be a way for people to delay many of these age-related diseases. Dr. Naidoo asserts that, “Sleep is a basic need that is made secondary to work schedules and some leisure activities for many adults” and “ It is imperative to educate the public about the very real damage of abnormal sleep/wake cycles.”29
Life extentionists hearing the work of these scientists can be eager to see the results applied immediately. In some cases this is possible, such as getting more sleep to reduce ER stress.
In most cases, however, we should appreciate that the research results are leading scientists closer to developing therapies to eventually enable humans to gain greater control over aging. While more research is required, the exponential rate of understanding as to why we age, and what can be done to slow and eventually reverse it, provides a tantalizing glimpse into a future where humans will live significantly longer without suffering early onset of degenerative disease.
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- Friedman DB, Johnson TE. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics. 1988 Jan;118(1):75-86.
- Brown-Borg HM, Borg KE, Meliska CJ, Bartke A. Dwarf mice and the ageing process. Nature. 1996 Nov 7;384(6604):33.
- Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999 Oct 1;13(19):2570-80.
- Kenyon C. The plasticity of aging: insights from long-lived mutants. Cell. 2005 Feb 25;120(4):449-60.
- Boily G, Seifert EL, Bevilacqua L, et al. SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS One. 2008 Mar 12;3(3):e1759.
- Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L. Effects of resveratrol on life span in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev. 2007 Oct;128(10):546-52.
- Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschöp MH. Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9793-8.
- Flick F, Lüscher B. Regulation of sirtuin function by posttranslational modifications. Front Pharmacol. 2012;3:29.
- Kanfi Y, Peshti V, Gil R, et al. SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell. 2010 Apr;9(2):162-73.
- Kanfi Y, Naiman S, Amir G, et al. The sirtuin SIRT6 regulates life span in male mice. Nature. 2012 Feb 22;483(7388):218-21.
- Mostoslavsky R, Chua KF, Lombard DB, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006 Jan 27;124(2):315-29.
- Lombard DB, Miller RA. Ageing: Sorting out the sirtuins. Nature. 2012 Mar 7;483(7388):166-7.
- Mao Z, Hine C, Tian X, et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science. 2011 Jun 17;332(6036):1443-6.
- Mao Z, Tian X, Van Meter M, Ke Z, Gorbunova V, Seluanov A. Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence. Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11800-5.
- Budovskaya YV, Wu K, Southworth LK, et al. An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in C. elegans. Cell. 2008 Jul 25;134(2):291-303.
- Brack AS, Conboy MJ, Roy S, et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 2007 Aug 10;317(5839):807-10.
- 17. Cheong C, Hong KU, Lee HW. Mouse models for telomere and telomerase biology. Exp Mol Med. 2003 Jun 30;35(3):141-53.
- Baker DJ, Jeganathan KB, Cameron JD, et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat Genet. 2004 Jul;36(7):744-9.
- Matsumoto T, Baker DJ, d’Uscio LV, Mozammel G, Katusic ZS, van Deursen JM. Aging-associated vascular phenotype in mutant mice with low levels of BubR1. Stroke. 2007 Mar;38(3):1050-6.
- 20. Baker DJ, Perez-Terzic C, Jin F,et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol. 2008 Jul;10(7):825-36.
- Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 2;479(7372):232-6.
- Naidoo N, Ferber M, Master M, Zhu Y, Pack AI. Aging impairs the unfolded protein response to sleep deprivation and leads to proapoptotic signaling. J Neurosci. 2008 Jun 25;28(26):6539-48.
- Naidoo N. ER and aging-Protein folding and the ER stress response. Ageing Res Rev. 2009 Jul;8(3):150-9.
- Naidoo N, Giang W, Galante RJ, Pack AI. Sleep deprivation induces the unfolded protein response in mouse cerebral cortex. J Neurochem. 2005 Mar;92(5):1150-7.
- Brown MK, Naidoo N. The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol. 2012;3:263.
- Devries-Seimon T, Li Y, Yao PM, et al. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. J Cell Biol. 2005 Oct 10;171(1):61-73.
- Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004 Oct 15;306(5695):457-61.
- Kim MK, Kim HS, Lee IK, Park KG. Endoplasmic reticulum stress and insulin biosynthesis: a review. Exp Diabetes Res. 2012;2012:509437.
- Singletary KG, Naidoo N. Disease and degeneration of aging neural systems that integrate sleep drive and circadian oscillations. Front Neurol. 2011;2:66.