The year is 2035. As a longtime Life Extension member, you have managed to live in good health until the age of 95. In 2010, you began to benefit from new therapies such as the transplantation of young stem cells into your blood and failing organs. These therapies protected you from killer diseases and premature aging, but were only a partial solution to your problems. Now your biological clock is starting to take its toll. Your cognitive powers are fading, your arteries are beginning to harden, your muscles are weakening, and your energy has begun to ebb.
In 2035, it is apparent that major breakthroughs are on the horizon: gene therapies to prevent aging; intelligent nanorobots to repair dysfunctional brain cells; neurostimulatory therapies to regenerate organs and other body parts; young tissues developed from stem cells to rejuvenate life systems; and new technologies to improve vision, hearing, strength, intelligence, sexual prowess, and other attributes.
Unfortunately, it is also apparent that it will still take decades to fully implement these advanced breakthroughs, which will be too late for you. The thought has begun to cross your mind that your generation might be the last to face death before a greatly extended healthy life span becomes commonplace.
A Life-Saving Voyage into the Future
However, all is not lost. Suspended animation, an advanced technology that was perfected in 2030, is readily available at hospitals throughout the world. After you go through this life-saving procedure to stop death in its tracks, you will be cared for at Timeship, a spectacular building on a beautiful site in the US (www.timeship.org).
|Figure 1. Model of Timeship created by architect Stephen Valentine.|
A month later, you are admitted to UCLA Medical Center, where your temperature is gradually lowered to -110 degrees Celsius (-110° C) without ice forming within your body, in a process called vitrification. Before long, you are in a state of biostasis within an insulated capsule. You are ready for a life-saving voyage into the future.
Your capsule is then placed into a transport container, which is loaded on to a high-speed, magnetically driven train, which takes you to Timeship, where you will be lowered via an automated system into a geometric honeycomb structure that already contains some of your relatives and friends. (Figs. 1,2.)
At Timeship, your body will undergo a stabilization process called annealing, as your temperature is lowered very slowly to -145° C. You will then be cared for with thousands of other patients until the technology has been developed to restore you to health and youthful vigor. Timeship also contains banks of cryopreserved cells, tissues, and organs for use in medicine, as well as laboratories where ongoing research is developing methods to revive and rejuvenate you.
Your decades of support for the Life Extension Foundation have clearly paid off. In the 1980s, Life Extension began to fund research to control aging, cure killer diseases, and achieve suspended animation. Life Extension is now funding research at Timeship to restore you to life, health, and youthful vigor. Because of Life Extension, you now have your own very special place in a unique, futuristic ship that is hurtling into time!
|Figure 2. Cross-sectional drawing of Timeship by architect Stephen Valentine.|
This scenario is based on path-breaking research now being funded by the Life Extension Foundation. Life Extension annually funds more than $6 million of research aimed at therapies to extend your life span. We have a visionary plan to make it possible for you to live in good health for centuries. We want to cure you of the ravages of aging and liberate you from the bonds of mortality. In the long run, we are striving for physical immortality.
Aging: Our Number-One Enemy
Aging is the process by which we die. Unless we die in youth, we are subject to the ravages of aging, which depletes our strength, flexibility, cognitive abilities, sexual prowess, coordination, and ability to fight off killer diseases. Even if we manage to avoid heart disease, stroke, cancer, and other killers, we are programmed to lose our health, vitality, and life because of the progressive physical destruction caused by aging. In short, we grow old, suffer, and die.
Life Extension’s plan to conquer aging focuses on the study of experimental models of life-span extension. Since aging causes us to die, the best measure of aging is how long we live. In the last 75 years, scientists have found that they can extend life span in a variety of ways. At Life Extension, our primary interest is in methods that extend maximum life span in mammals.
Extending Maximum Life Span
There are currently two experimental models for the extension of maximum life span in mammals: caloric restriction (CR), which has been studied in mice, rats, dogs, and monkeys; and dwarfism in Ames and Snell mice.
Calorie-restricted animals are fed a very low-calorie diet enriched with protein, vitamins, minerals, and essential fatty acids, which induces undernutrition without malnutrition. The first studies showing that CR can extend maximum life span were conducted with rats in the 1930s by Clive M. McCay of Cornell University. McCay found that CR could extend the maximum life span of rats by up to 50%, while preventing cancer and other age-related diseases. McCay’s experimental rats were far more youthful and vigorous at advanced ages than rats fed a normal diet.
|Figure 3. The mouse on the left has been on a calorie-restricted diet and is lighter, healthier, and more youthful in appearance and behavior than his normally fed counterpart. Both mice are 20 months of age.|
Over the last 75 years, scientists around the world have conducted dozens of CR experiments with similar results. They have found further evidence of CR’s ability to slow aging and extend youth, including its ability to prevent the immune dysfunctions of old age, improve DNA repair, reduce damaging free radical activity, lower glucose and insulin levels, maintain fertility at advanced ages, boost energy levels, reduce the accumulation of damaged proteins, inhibit inflammatory processes, counteract neurodegeneration, and prevent age-related decline in the health-building hormone DHEA (dehydroepiandrosterone). CR also prevents, postpones the incidence of, and reduces the severity of diseases that kill mammals, such as cancer, kidney disease, and cardiovascular disease.1
At advanced ages, calorie-restricted animals are thinner, smaller, and more youthful looking than normally fed animals. The most striking difference between CR and normally fed animals is their activity level. Thirty-month-old, normally fed mice, which are roughly equivalent to 80-year-old humans, are sluggish, bloated, and often have malignant tumors. By contrast, 30-month-old CR mice exercise vigorously, often in acrobatic fashion, and are highly inquisitive. (Fig. 3.)
The subjects of CR experiments have included long-lived mammals such as monkeys. In two studies at the University of Wisconsin in Madison and the National Institute on Aging in Baltimore, calorie-restricted monkeys have displayed the youthful characteristics of CR mice and rats, though it is still too early to determine whether their maximum life span will be extended.
The other life-span extension model we have been studying is Ames dwarf mice, which have a single gene mutation that interferes with their anterior pituitary function, causing deficiencies in growth hormone, prolactin, and thyroid-stimulating hormone.2 It is believed that the deficiency of growth hormone (and insulin-like growth factor 1, which is made in response to growth hormone) may be the primary reason these mice live so much longer than normal. According to one finding that suggests this, mice that cannot respond to growth hormone because their growth hormone receptor gene has been knocked out live up to 55% longer than normal mice.3 Recently, Dr. Andrzej Bartke and his colleagues at Southern Illinois University showed that Ames dwarf mice, which live 50% longer than normal Ames mice, had their life span extended another 25% by caloric restriction.4 We have been collaborating with Dr. Bartke on studies of gene expression in Ames dwarf mice.
Because severe, long-term caloric restriction is not practical in humans, our strategy has been to search for drugs, nutrients, and other therapies capable of extending life span in mammals, or CR mimetics. We quickly concluded that we needed a shortcut to discovering CR mimetics. Life-span studies—even in relatively short-lived species such as mice—simply take too long and are too expensive to make it likely that we can find true CR mimetics in the foreseeable future.
Genes That Extend Maximum Life Span
In 1999, we came across a new experimental method to help search for CR mimetics: high-density microarrays, or gene chips. Drs. Richard Weindruch and Tomas Prolla of the University of Wisconsin published a study of gene expression in the muscles of both normal and CR mice.5 Gene chips enabled the scientists to rapidly measure changes in the expression of more than 6,000 genes. Not only was this a dramatic shortcut to finding genes involved in extending maximum life span, but it also provided an approach to screening for CR mimetics.
Before long, Life Extension was funding gene-chip CR studies at the University of California, Riverside, under the direction of Drs. Stephen R. Spindler and Joseph Dhahbi. Life Extension has now been funding gene-expression research over the past five years, initially at the University of California and then at other laboratories in California and in other states and countries. Most of our funding has been through BioMarker Pharmaceuticals (www.biomarkerinc.com), a company created to discover genetic bio-markers of aging in order to develop anti-aging therapies in humans.
Initial Gene-Expression Studies
The initial gene-expression studies we funded produced provocative results that have been published in scientific journals. In 2003, we decided that we needed to conduct new and larger studies because very few animals were used in the initial studies and because they were conducted with gene chips that could measure the expression of only about 6,000 or 12,000 genes. By 2003, more advanced gene chips were available that could measure the entire mouse genome of 39,000 transcripts, including 34,000 genes. BioMarker established a laboratory in northern California and developed collaborations with Stanford University, Gorilla Genomics, the Chinese Academy of Sciences, and the Children’s Hospital Oakland Research Institute, where we now have access to sophisticated new facilities and greater scientific expertise.
Before we look at the gene-expression and other studies Life Extension is now funding, here is a summary of some findings from the initial studies we funded:
- Long-term caloric restriction induces many changes in gene expression in mice.6 Some of the changes involve decreasing gene activity, while others involve increasing gene activity. They vary to some extent according to the type of tissue tested. Thus far, CR-induced gene-expression changes have been studied in liver, heart, brain, and muscle tissue. These changes involve genes responsible for antioxidant defenses against free radical activity, DNA repair, insulin and glucose regulation, and other functions. Many changes occur in signal transduction-related genes, which regulate other genes.
- There are also many changes in gene expression in long-lived Ames dwarf mice. Some of these changes are the same as those found in CR mice, while others are different. Ames dwarf mice fed a CR diet live longer than CR mice or normally fed Ames dwarf mice. These findings suggest that the benefits of anti-aging therapies based on these two models may be additive. The ability to completely mimic the gene changes found in CR mice could enable you to live to be 150, while adding the ability to mimic the gene changes in Ames dwarf mice could add another 20 years to your life span. Thus, future therapies based on both models of extended life span might enable you to live to 170.
- Most of the gene-expression changes caused by long-term CR occur within four to eight weeks after animals are placed on a CR diet.7 These changes in gene expression occur around the same time the mice shift toward a new, longer life-span potential. The rapidity with which these gene changes are expressed suggests that their measurement could be a quick, inexpensive, and effective way of discovering potential anti-aging therapies. Once promising therapies have been identified, we can study the effects of these therapies on maximum life span, other biomarkers of aging, and age-related diseases.
- Caloric restriction can extend maximum life span in old mice, not just in young and middle-aged mice. Moreover, the rapid changes in gene expression induced by CR produce rejuvenation effects in these mice.8 In recognition of these findings, Dr. Spindler of BioMarker and the University of California, Riverside, was presented with the first Methuselah Mouse Rejuvenation Award in November 2004 at the annual Gerontological Society of America meeting in Washington, DC. Dr. Aubrey de Grey of Cambridge University, who chairs the Methuselah Foundation (www.methuselahfoundation.org), presented the reward. Dr. de Grey acknowledged the Life Extension Foundation for its funding of this research. It may be that anti-aging therapies developed from this truly groundbreaking research will be able to rejuvenate old people, not just slow down aging in younger people.
- The drug metformin, long prescribed as a treatment for diabetes, produced many of the gene-expression changes induced by CR after being given to adult mice for eight weeks. Treatment with metformin matched 75% of the gene-expression changes induced by long-term CR and 92% of the changes induced by short-term (eight-week) CR. Both metformin and CR reduced glucose and insulin blood levels, inhibited cancer cell proliferation, extended life span, and prevented mammary tumors in female transgenic mice.9
New Research Equipment
After our laboratory was launched in northern California in late 2003, a colony of naturally long-lived mice was established for future studies. We purchased young mice and allowed a group of these mice, which had been put on a CR diet, to mature to adulthood.
We also purchased or leased new equipment and state-of-the-art informatics and statistical analysis software to help us conduct future studies more effectively. The equipment we obtained includes:
1. The Agilent 2100 Bioanalyzer, a microfluidics-based platform that uses lab-on-a-chip technology for analysis of DNA, RNA, proteins, and cells. (Fig. 4.)
2. The NanoDrop® ND-1000A UV/Vis Spectrophotometer, a highly accurate system designed for extremely small specimens (1-2 microliters). (Fig. 5.)
3. The Arcturus Veritas™ Automated Laser Capture Microdissection and Laser Cutting System, a highly advanced technology that enables us to isolate single or specific types of cells through ultraviolet dissection. (Fig. 6.)
|Figure 4. Agilent 2100 Bioanalyzer.
||Figure 5. NanoDrop® ND-1000A UV/Vis Spectrophotometer.
||Figure 6. Arcturus Veritas™ Automated Laser Capture|
Microdissection and Laser Cutting System.