Rejuvenation (aging)

Rejuvenation is the procedure of reversing the aging process, thus regaining youth. As people get older, their health worsens, strength and intelligence are thought to diminish, beauty is thought by many to go away. Historically, people in all societies have looked for a way to regain the qualities of youth. In the future however, rejuvenation may become reality through stem cells, biochemical repair or nanotechnology.

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Historical and Cultural Background

Various myths tell the stories about the quest for rejuvenation. It was believed that magic or intervention of a supernatural power can bring back the youth and many mythical adventurers set out on a journey to do that, for themselves, their relatives or some authority that sent them.

An ancient Chinese emperor actually sent out ships of young men and women to find a pearl that would rejuvenate him. This led to a myth among modern Chinese that Japan was founded by these people.

In some religions people were to be rejuvenated after death prior to placing them in heaven.

The stories continued well into the 16th century. A famous Spanish explorer Juan Ponce de León led the expedition around the Caribbean islands and into Florida to find the Fountain of Youth. Led by the rumours, the expedition continued the search and many perished. The Fountain was nowhere to be found as locals were unaware of its exact location.

Since the emergence of philosophy, sages and self-proclaimed wizards always made enormous efforts to find the secret of youth, both for themselves and for their noble patrons and sponsors. It was widely believed that some potions may restore the youth.

Another commonly cited approach was attempting to transfer the essence of youth from young people to old. Some examples of this approach were sleeping with virgins or children (sometimes literally sleeping, not necessarily having sex), bathing in or drinking their blood.

The quest for rejuvenation reached its height with Alchemy. All around the Europe and also beyond alchemists were looking for the Philosopher's Stone, the mythical substance that, as it was believed, could not only turn lead into gold, but also prolong life and restore youth. Although the set goal was not achieved, Alchemy paved the way to the scientific method and so to the medical advances of today.

In fiction, there is an increasing amount of work being done on possibilities of rejuvenation treatments, and the effect this would have on society. Misspent Youth as well as the Commonwealth Saga by Peter F. Hamilton are one of the most well known examples of this, dealing with the short and long term effects of a near perfect 80 year old to 20 year old body change with mind intact. Also the Mars trilogy deals with a much more imperfect type of rejuvenation, including problems such as long term memory loss and sheer boredom that comes with such age. Also the post mortal characters in the Revelation Space series often illustrate this issue with long term or essentially infinite lifespans, sheer boredom induces them to undertake activities of extreme risk.

Modern developments

According to modern science, there are no natural laws preventing successful rejuvenation. Aging is an accumulation of damage to macromolecules, cells, tissues and organs. If any of that damage can be repaired, the result is rejuvenation.

There have been many experiments which have been shown to increase the maximum life span of laboratory animals, thereby achieving life extension. A few experimental methods such as replacing hormones to youthful levels have had considerable success in partially rejuvenating laboratory animals and humans. There are at least eight important hormones that decline with age: 1. human growth hormone (HGH); 2. the sexual hormones: testosterone or estrogen/progesterone; 3. erithropoietin EPO; 4. insulin; 5. DHEA; 6. melatonin; 7. thyroid; 8. pregnenolone. In theory, if all or some of these hormones are replaced, the body will respond to them as it did when it was younger, thus repairing and restoring many body functions. This seems to be borne out in hundreds of thousands of persons who have replaced hormones for many years, especially human growth hormone (HGH, a.k.a. GH).

Most attempts at genetic repair have traditionally involved the use of a retrovirus to insert a new gene into a random position on a chromosome. But by attaching zinc fingers (which determine where transcription factors bind) to endonucleases (which break DNA strands) homologous recombination can be induced to correct and replace defective (or undesired) DNA sequences. The first applications of this technology are to isolate stem cells from the bone marrow of patients having blood disease mutations, to correct those mutations in laboratory dishes using zinc finger endonucleases and to transplant the stem cells back into the patients ^[1].

Regenerative medicine uses three different strategies:

1. Implantation of stem cells from culture into an existing tissue structure
2. Implantation of stem cells into a tissue scaffold that guides restoration or
3. Induction of residual cells of a tissue structure to regenerate the necessary body part.

A salamander can not only regenerate a limb, but can regenerate the lens or retina of an eye and can regenerate an intestine. For regeneration the salamander tissues form a blastema by de-differentiation of mesenchymal cells, and the blastema functions as a self-organizing system to regenerate the limb ^[2].

Yet another option involves cosmetic changes to the individual to create the appearance of youth. These are generally superficial and do little to make the person healthier or live longer, but the real improvement in a person's appearance may elevate their mood and have positive side effects normally correlated with happiness. Cosmetic surgery is a large industry offering treatments such as removal of wrinkles ("face lift"), removal of extra fat (liposuction) and reshaping or augmentation of various body parts (abdomen, breasts, face).

There are also, as always in history, many fake rejuvenation products that do not work. Chief among these are powders and sprays and gels and homeopathic that claim to be "growth hormone". Authentic growth hormone can only be injected, because the 191 amino-acid protein is too large to be absorbed through the mucous membranes, and would break up in the stomach if it is swallowed.

Strategies for Engineered Negligible Senescence (SENS)

The leading modern exponent of scientific rejuvenation is the biomedical gerontologist Dr. Aubrey de Grey. He calls his project to reverse the damage we call aging SENS (Strategies for Engineered Negligible Senescence). He has proposed seven strategies for what he calls the "seven deadly sins":

1. Cell loss can be repaired (reversed) just by suitable exercise in the case of muscle. For other tissues it needs various growth factors to stimulate cell division, or in some cases it needs stem cells.
2. Senescent cells, can be removed by activating the immune system against them. Or they can be destroyed by gene therapy to introduce "suicide genes" that only kill senescent cells.
3. Protein cross-linking can largely be reversed by drugs that break the links. But to break some of the cross-links we may need to develop enzymatic methods.
4. Extracellular garbage (like amyloid) can be eliminated by vaccination that gets immune cells to "eat" the garbage.
5. For intracellular junk we need to introduce new enzymes, possibly enzymes from soil bacteria, that can degrade the junk (lipofuscin) that our own natural enzymes cannot degrade.
6. For mitochondrial mutations the plan is not to repair them but to prevent harm from the mutations by putting suitably modified copies of the mitochondrial genes into the cell nucleus by gene therapy. The mitochondrial DNA experiences a high degree of mutagenic damage because most free radicals are generated in the mitochondria. A copy of the mitochondrial DNA located in the nucleus will be better protected from free radicals, and there will be better DNA repair when damage occurs. All mitochondrial proteins would then be imported into the mitochondria.
7. For cancer (the most lethal consequence of mutations) the strategy is to use gene therapy to delete the genes for telomerase and to eliminate telomerase-independent mechanisms of turning normal cells into "immortal" cancer cells. To compensate for the loss of telomerase in stem cells we would introduce new stem cells every decade or so.

Dr. de Grey has created the Methuselah Mouse Prize, which awards money to researchers who can rejuvenate mice.

Aubrey de Grey's claim that the only significant effect of nuclear DNA (nDNA) damage is cancer is open to dispute, and this impacts both of his last two strategies (neither of which is appropriately described as "repair"). Evidence of significantly reduced oxidative damage to mitochondrial DNA (mtDNA) and negligible oxidative damage to nDNA in calorie restricted rats ^[3] is misleading because DNA repair capability declines with age. Thymine dimer removal (a form of DNA repair) is about five times greater in newborn fibroblasts than in fibroblasts from the elderly ^[4]. So although DNA damage other than mutation (cancer), may be small in the young, it increases greatly with age. Moving mtDNA into the nucleus would not be as beneficial as he presumes if nDNA is subject to such a decline in DNA repair with age.

A comparison of the heart mitochondria in rats (4-year lifespan) and pigeons (35-year lifespan) showed that pigeon mitochondria leak fewer free radicals than rat mitochondria, despite the fact that both animals have similar metabolic rate and cardiac output. Pigeon heart mitochondria (oxidative phosphorylation protein Complexes I & III) showed a 4.6% free radicals leak compared to a 16% free radical leak in rat heart mitochondria ^[5]. Rather than copy mtDNA into the nucleus, it may be a more effective strategy to reduce free radical production in mitochondria by making human Complex I more like the Complex I found in birds, by copying from the bird genome. A comparison of 7 non-primate mammals (mouse, hamster, rat, guinea-pig, rabbit, pig and cow) showed that the rate of mitochondrial superoxide and hydrogen peroxide production in heart and kidney were inversely correlated with maximum life span ^[6]. A similar study of 8 non-primate mammals showed a direct correlation between maximum lifespan and oxidative damage to mtDNA in heart & brain. There was a 4-fold difference in levels of oxidative damage and a 13-fold difference in longevity, supportive of the idea that mtDNA oxidative damage is not the only cause of aging ^[7].

The segmental progerias ("accelerated aging" diseases) are part of the evidence that the weakest link in extending lifespan is DNA repair -- along with the fact that DNA repair capability correlates with maximum lifespan in mammals ^[8]. There is much that could be done to improve DNA repair both in the nucleus and in the mitochondria. We could study organisms like the bacterium Deinococcus radiodurans ^[9] and adapt their enzymes to our cells. Thus, improved DNA repair and reduced free radical production (by Complex I proteins taken from birds) may be much more cost effective strategies than SENS for reducing aging-damage, extending maximum lifespan and preventing cancer.

Scientific Journal

• Rejuvenation Research Editor: Aubrey de Grey. Publisher: Mary Ann Liebert, Inc. ISSN 1549-1684 - Published Quarterly.

See also

• American Academy of Anti-Aging Medicine
• Aubrey de Grey
• Biogerontology
• Biological immortality
• DNA repair
• Engineered negligible senescence
• Facial rejuvenation
• Fountain of Youth
• Immortality
• Indefinite lifespan
• Life extension
• Methuselah Mouse Prize
• Nanomedicine
• SAGE KE
• Senescence
• Tissue engineering
• Therapeutic cloning

References

1. ^ Jocelyn Kaiser (2005). "Gene therapy. Putting the fingers on gene repair". SCIENCE 310 (5756): 1894-1896. PMID 16373552.
2. ^ Brockes JP, Kumar A (2005). "Appendage regeneration in adult vertebrates and implications for regenerative medicine". SCIENCE 310 (5756): 1919-1923. PMID 16373567.
3. ^ Lopez-Torres M, Gredilla R, Sanz A, Barja G (2002). "Influence of aging and long-term caloric restriction on oxygen radical generation and oxidative DNA damage in rat liver mitochondria". FREE RADICAL BIOLOGY & MEDICINE 32 (9): 882-889. PMID 11978489.
4. ^ Goukassian D, Gad F, Yaar M, Eller MS, Nehal US, Gilchrest BA (2000). "Mechanisms and implications of the age-associated decrease in DNA repair capacity". THE FASEB JOURNAL 14 (10): 1325-1334. PMID 10877825.
5. ^ Herrero A, Barja G. (1997). "Sites and mechanisms responsible for the low rate of free radical production of heart mitochondria in the long-lived pigeon". MECHANISMS OF AGING AND DEVELOPMENT 98 (2): 95-111. PMID 9379714.
6. ^ Ku HH, Brunk UT, Sohal RS. (1993). "Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species". FREE RADICAL BIOLOGY & MEDICINE 15 (6): 621-627. PMID 8138188.
7. ^ Barja G, Herrero A. (2000). "Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals". THE FASEB JOURNAL 14 (2): 312-318. PMID 10657987.
8. ^ Cortopassi GA, Wang E. (1996). "There is substantial agreement among interspecies estimates of DNA repair activity". MECHANISMS OF AGING AND DEVELOPMENT 91 (3): 211-218. PMID 9055244.
9. ^ White O, Eisen JA, Heidelberg JF, Hickey EK, Peterson JD, Dodson RJ, Haft DH, Gwinn ML, Nelson WC, Richardson DL, Moffat KS, Qin H, Jiang L, Pamphile W, Crosby M, Shen M, Vamathevan JJ, Lam P, McDonald L, Utterback T, Zalewski C, Makarova KS, Aravind L, Daly MJ, Minton KW, Fleischmann RD, Ketchum KA, Nelson KE, Salzberg S, Smith HO, Venter JC, Fraser CM (1999). "Genome sequence of the radioresistant bacterium Deinococcus radiodurans R1". SCIENCE 286 (5444): 1571-1577. PMID 10567266.