Life Extension Magazine®

Issue: Sep 2011

Programming Genes to Extend Life Span

The phenomenon known as gene expression, or how genes turn “on” and “off” over the course of your lifetime, lies at the core of the aging process. Restoring youthful gene expression is vital to extending healthy life span. Avant-garde scientists talk about the latest strategies for reprogramming genes and boosting longevity.

By Charles Platt.

Programming Genes to Extend Life Span

Skeptics who question whether aging can be conquered often make the problem appear more complicated than it may be.

Differences in gene expression between young people and older people are a well-documented fact.1,2 In simple terms, almost all the processes in our bodies work better when we are young. Many of us make it to age 50 or beyond before changes in gene expression manifest themselves as serious illnesses.

In the future, we will be able to control (i.e., reprogram) our genes as readily as we do our computers. Some scientists believe that as a result of this, humans may theoretically remain young and healthy for very much longer than they do today.

Restoration of youthful gene expression would enable cells, tissues, and organs to grow younger as opposed to the degenerative downward spiral that now occurs.

We already exert some control over our gene expression with the lifestyle we choose and the supplements we ingest such as fish oil, vitamin D, pterostilbene, and resveratrol.

Scientists have only recently come to the realization that foods, nutrients, and medications that make us healthier do so in part because they induce the expression of health-promoting genes and reduce the expression of disease-promoting genes. Consumption of toxic foods and chemicals, on the other hand, induces the expression of disease-promoting genes and reduces the expression of health-promoting genes.3-5

Those who argue about cumulative damage to the body forget how healthy most children are, how they get healthier as they mature into young adulthood, and only then begin to decline. Youthful gene expression enables most children to maintain a relatively good state of health—until the bad genes overexpress while beneficial ones underexpress—and pathologic aging ensues.

This article focuses on the possibility of altering gene expression for the purposes of extending healthy life span. This science is in its infancy, but it is clearly leading to the time when scientists will develop genetic engineering and stem cell therapies that will enable physicians to reverse aging and help us to grow younger and healthier with advancing age.

Rewriting the Aging Program

Rewriting the Aging Program

We live in an exciting time. Many scientists now agree that there are genetic mechanisms that control the aging process, and the implication of this is that it will eventually become possible to reverse aging and cure the diseases of aging.

We still have no comprehensive model explaining how aging occurs, but we know a great deal about how aging manifests itself, and we are beginning to learn how to reverse it.

This becomes evident to anyone who reads The Future of Aging, a massive scholarly volume that includes articles by some of the most prominent researchers in the field.6 In June of this year I spoke to Dr. Gregory Fahy, the editor-in-chief of the book, while he was attending the annual American Aging Association meeting. “One of the purposes of this book was to present the case for genetic causes of aging in a way that my colleagues will find difficult to ignore,” Dr. Fahy told me.

Why, then, do some scientists—even within the aging field—remain skeptical?

“Aging is not just due to local wear and tear,” Fahy concludes. “For example, in flies and worms, it has been shown to be a process controlled in significant part by the brain.”6

Dr. Fahy’s outlook is strongly supported by much work on C. elegans, a small nematode (worm) that is widely used by biologists because it is so easily studied. At the same time, like all living things, it has its own DNA, bearing some resemblance to our own. It also has organs, intestines, and ganglia (nerve cell clumps that operate in some cases like our brains), eats food and reproduces, making it an ideal model for testing genetic modifications. Fahy reports that in recent work, the Shmookler-Reis lab succeeded in creating a genetic variant of C. elegans that has ten times the normal life span of the standard organism.6 Cynthia Kenyon and her coworkers had previously reported a six-fold life span increase in Science magazine.7 These astonishing changes in longevity were entirely caused by reducing the expression of a few master genes.

Similarly, gene expression changes are the major explanation for the results reported by Dr. Michael Rose, who claims to have quadrupled the average life span of fruit flies merely by selective breeding.8 “The idea that aging is just a cumulative process of damage is fundamentally incorrect,” Rose commented when I spoke to him about his work. As a coauthor of the new book Does Aging Stop? from Oxford University Press, Rose points out that some organisms already cease to age late in life. “We have fly populations where 40% of the cohort stops aging,” he says.

What You Need to Know: Achieving Physical Immortality
Achieving Physical Immortality
  • Older and younger people demonstrate differences in gene expression.
  • Restoring youthful gene expression may help turn back the clock on aging and potentially extend healthy life span.
  • In animal models, scientists have dramatically extended life span by modulating the expression of a few genes.
  • Environmental influences such as diet and exercise may strongly influence gene expression and longevity.
  • Mimicking the effects of genes associated with extreme longevity may provide another avenue to lengthening life span.
  • Regenerative therapies developed from adult or embryonic stem cells seek to reverse aging by regenerating tissues or organs.
  • Nutrigenomics is the field of nutritional interventions developed on a genetic basis.
  • The field of anti-aging medicine is poised for tremendous growth and advancement in coming years, similar to what the field of computer science has seen in the past 60 years.

Why, then, do some scientists—even within the aging field—remain skeptical?

Dr. Rose suggests that processes in biology are making a transition from being described entirely by words to being defined by mathematics. “The less mathematical scientists are, the longer it takes for them to change their minds,” he says. “Words give you much more opportunity for self-deception. Mathematics allows predictions that can be verified. Galileo was influential because he replaced words with equations.”

Gregory Fahy sees biological conservatism as being simply a facet of human nature. “Most scientists tend to be scientifically conservative,” he says. “They’re thinking about their next experiment and not necessarily about the broader relationships between genes and aging. And most biologists are discovery-oriented, not intervention-oriented.”

Even biogerontologists may underestimate the meaning of the breakthrough work by scientists such as Robert Shmookler-Reis, Cynthia Kenyon, and Michael Rose. The traditional outlook is that genes only control a relatively small proportion of the aging process, often estimated at around 30%.9,10 After all, studies of identical twins have shown that genes only explain some of their differences in aging. “But of course, environmental influences such as diet and exercise can strongly influence gene expression!” Fahy comments. “My hypothesis is that if you can trace an aging process back far enough, there’s almost always a gene at the root of what you find.”

Intervening in Aging

Intervening in Aging

While we grow older waiting for a wider acceptance of genetic theories of aging, we can at least take advantage of the knowledge that already exists. Several genes, for instance, are known to be associated with extreme longevity.11,12 If we can mimic what they do in people who have ordinary genes, we may gain some valuable time. Drug approaches have already been pursued for this purpose, and dietary supplements may also be effective in this respect, as suggested by Rose.

But there are also many common genes that change their expression with aging in counterproductive ways, and we have tools by which we might be able to prevent and reverse these detrimental changes in ordinary genes. For example, Sangamo Biosciences is developing “zinc finger” proteins that can be used for this purpose, as reported on their web site.13 If their approach is fruitful, the zinc finger proteins could be targeted to specific cells by keying them to appropriate receptors, which would allow them to enter and therefore to turn a gene on or off in particular cells. Since only a relatively small number of master genes seem to be involved in controlling the aging process, a set of these modulators could be sufficient to facilitate greater human longevity.

One of the benefits could be the correction of a form of “cellular constipation” that may underlie a surprisingly large fraction of the aging process. Normally when proteins are damaged, the human body breaks them down into amino acids and rebuilds them, but the rate of autophagy (which means, literally, “self- eating”) diminishes in cells with age, allowing damage to accumulate with time. Researcher Ana Marie Cuervo, MD, PhD, has already engineered her own specific remedies to address this problem. A paper she coauthored describes work that has successfully rejuvenated the livers of mice.14 Very possibly, a similar approach could be applied to the brain.

Another problem that might be usefully addressed is the failure of damaged cells to die as they should through a normal process called apoptosis (programmed cell death). Rather than dying, the cells linger in the body and emit signals that promote overexpression of pro-inflammatory cytokines, or they mutate into cancer cells. By detecting inappropriate gene expression in such cells, it may be possible to re-activate apoptosis and get rid of them so they can be replaced with healthy young cells.

Cell Replacement Therapies

In the longer term we have realistic expectations for aging reversal, or regeneration. The promise of regenerative medicine (as espoused by Aubrey de Grey) has been greatly boosted by the prospect of therapies developed from embryonic and adult stem cells, or induced pluripotent stem cells (iPS) developed from an individual’s adult cells. Adult stem cells are already being used to develop therapies to regenerate tissues and organs. Embryonic stem cells have even greater potential for the development of anti-aging and anti-disease therapies because they can potentially be developed into any type of differentiated adult cells, which could then be transplanted into an aging, diseased, or injured person. The potential value of using iPS cells to develop new anti-aging therapies is that these cells are developed directly from the patient’s own adult cells without the need to form an early embryo. Since they have the same genes as the treated patient, they should not be rejected by the patient’s immune system.

Cell Replacement Therapies

Scientists including Dr. Michael West, the founder of Geron and current CEO of BioTime, Inc., have proved that embryonic stem cells can be created by inserting a person’s DNA into an ovum from a woman of reproductive age and then allowing that cell to develop into a very early embryo called a blastocyst, which is basically still just a ball of cells with a hollow cavity inside. Other scientists have proved that iPS cells can be developed from adult cells by exposing them to four genetic factors. There have been studies showing that iPS cells may not be as safe or as potent as embryonic stem cells, but Dr. West and associates recently demonstrated that some iPS cells may be as safe and potent as embryonic stem cells (see the interview with Michael West in the June 2010 issue of Life Extension Magazine® ).15 Dr. West is actively pursuing the potential of partially differentiated stem cells (progenitor cells) to regenerate or replace almost any type of cellular damage. Dr. West and his colleagues are attempting to develop a therapy to rejuvenate the vascular and immune system in old mice, which is being funded by the Life Extension Foundation®. (Refer to article Research Funded by Life Extension® Could Lead to Therapies That Reverse Human Aging for details.)

Such research efforts are attempting to reverse aging and extend healthy life span essentially by turning back the clock of aging changes in gene expression in aging cells. However, we have no way of knowing which approaches will be most beneficial. “We’re still in the blind-men-and-the-elephant stage,” comments Dr. Gregory Benford, referring to the multiple approaches being used by different researchers attempting to understand and control the aging process. Benford is a physicist who helped to capitalize Genescient, a company that is developing products based on the work of Michael Rose. “For the next 5 to 10 years,” he says, “we’ll be doing nutrigenomics—supplements developed on a genetic base.” After that, there will be a better prospect for more radical interventions.

Validation for Genetic Causes of Aging

Dr. Fahy encountered recent validation of his outlook about the genetic mechanisms involved in aging at this year’s American Aging Association conference.

Russian researchers presented evidence that the presence or absence of 27 specific SNPs (genetic variations called single-nucleotide polymorphisms) largely in certain introns (silent portions of genes that may help to control gene expression) could determine whether you are likely to live to 77 or 97.

Conclusion

Some of us still remember the Commodore Pet, the first desktop computer, marketed in 1977, with four kilobytes of memory.16 Aside from playing very primitive video games on its tiny screen, consumers had difficulty imagining what they could use it for. Going back just a little further, a state-of-the-art computer at MIT occupied more than two rooms and its processor consisted of 18,000 vacuum tubes.17 And this was a mere 60 years ago. Today, all of us have routine access to computers that are more than a million times as powerful while being small enough to hold in the palm of the hand, and we have difficulty imagining life without computing devices.

One mission of Life Extension Foundation® is to encourage public awareness that similar huge transformations are possible in the biosciences. Now that the human genome has been sequenced, we believe that the aging process can be controlled and biological death can be postponed or even eliminated, if sufficient resources are devoted to this challenge.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References
  1. Raue U, Slivka D, Jemiolo B, Hollon C, Trappe F. Myogenic gene expression at rest and after a bout of resistance exercise in young (18–30 yr) and old (80–89 yr) women. J Appl Physiol. 2006 Jul;101(1):53-9.
  2. Li Y, Liu Y, Stricklanda FM, Richardson B. Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes. Exp Gerontol. 2010 Apr;45(4):312-22.
  3. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003 Mar;33 Suppl:245-54.
  4. Cooney C, Dave A, Wolff G. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr. 2002 Aug;132(8 Suppl):2393S-2400S.
  5. Funk JL, Frye JB, Ovarzo JN, et. al. Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis. Arthritis Rheum. 2006 Nov;54(11):3452-64.
  6. Fahy GM, Coles SC, Harris SB, eds. The Future of Aging: Pathways to Human Life Extension. 1st ed. New York, NY: Springer Science and Business Media; 2010.
  7. Arantes-Oliveira N, Berman JR, Kenyon C. Healthy animals with extreme longevity. Science. 2003 Oct 24;302(5645):611.
  8. Mueller LD, Rauser CL, Roses MR. Does Aging Stop? Oxford University Press;2011.
  9. Christensen K, Vaupel JW. Determinants of longevity: genetic, environmental and medical factors. Intern Med. 1996 Dec;240(6):333-41.
  10. Hayakawa K, Shimizu T, Ohba Y, et al. Intrapair differences of physical aging and longevity in identical twins. Acta Genet Med Gemellol (Roma). 1992;41(2-3):177-85.
  11. Perls T. Genetic and environmental influences on exceptional longevity and the AGE nomogram. Ann NY Acad Sci. 2002 Apr;959:1-13.
  12. Heijmansa BT, Westendorpb RG, Slagboom PE. Common gene variants, mortality and extreme longevity in humans. Exp Gerontol. 2000 Sep;35(6-7):865-77.
  13. Available at: www.sangamo.com/technology/zfp-transcription-factors.html. Accessed June 20, 2011.
  14. Bejarano1 EJ, Cuervo AM. Chaperone-mediated autophagy. Proc Am Thorac Soc. 2010 Feb;7(1):29-39.
  15. Fahy GF, Kent S. Immortal stem cells for anti-aging therapies. An interview with Michael D. West, PhD. Life Extension Magazine®. 2010 Jun;16(6):26-32.
  16. Available at: www.commodorepet.org/. Accessed June 20, 2011.
  17. Available at: www.old-computers.com/museum/computer.asp?c=1047&st=1. Accessed June 20, 2011.

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