Rejuvenation

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Rejuvenation is a medical discipline focused on the practical reversal of the aging process. [1]

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Rejuvenation is distinct from life extension. Life extension strategies often study the causes of aging and try to oppose those causes in order to slow aging. Rejuvenation is the reversal of aging and thus requires a different strategy, namely repair of the damage that is associated with aging or replacement of damaged tissue with new tissue. Rejuvenation can be a means of life extension, but most life extension strategies do not involve rejuvenation.

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 youth and many mythical adventurers set out on a journey to do that, for themselves, their relatives or some authority that sent them anonymously.

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. The Spanish explorer Juan Ponce de León led an expedition around the Caribbean islands and into Florida to find the Fountain of Youth. Led by the rumors, 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), [2] bathing in or drinking their blood.

The quest for rejuvenation reached its height with alchemy. All around 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.[ citation needed ]

Serge Abrahamovitch Voronoff was a French surgeon born in Russia who gained fame for his technique of grafting monkey testicle tissue on to the testicles of men while working in France in the 1920s and 1930s. This was one of the first medically accepted rejuvenation therapies (before he was proved to be wrong around 1930–1940). The technique brought him a great deal of money, although he was already independently wealthy. As his work fell out of favor, he went from being a highly respected surgeon to a subject of ridicule. By the early 1930s, over 500 men had been treated in France by his rejuvenation technique, and thousands more around the world, such as in a special clinic set up in Algiers. [3] Noteworthy people who had the surgery included Harold McCormick, chairman of the board of International Harvester Company, [4] and the aging premier of Turkey. [5]

Swiss doctor Paul Niehans, who was one of the fathers of cellular therapy, developed in 1931–1949 years the so-called Fresh cell therapy. Fresh cell therapy is mainly the use of live animal embryo organs cells which are injected into the patient with the purpose of achieving a revitalizing effect. These cells are generally extracted from sheep’s fetuses because in comparison to other animals, like pigs, rabbits and cows, sheep are clean animals and rarely contract diseases. Of course animal cells are not able to be included in human tissue, but they can secrete factors for rejuvenating. That's why this rejuvenation technology, despite the harsh criticism [6] [7] is practiced to this day. [8]

Rejuvenation technology and its effects on individuals and society have long been a subject of science fiction. The Misspent Youth and Commonwealth Saga by Peter F. Hamilton are among 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. The less perfect rejuvenation featured in the Mars trilogy by Kim Stanley Robinson results in long-term memory loss and sheer boredom that comes with extreme age. The post-mortal characters in the Revelation Space series have long-term or essentially infinite lifespans, and sheer boredom induces them to undertake activities of extreme risk.

Modern developments

Aging is the accumulation of damage to macromolecules, cells, tissues and organs in and on the body which, when it can no longer be tolerated by an organism, ultimately leads to its death. 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,[ citation needed ] 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. A 2011 experiment involved breeding genetically manipulated mice that lacked an enzyme called telomerase, causing the mice to age prematurely and suffer ailments. When the mice were given injections to reactivate the enzyme, it repaired the damaged tissues and reversed the signs of aging. [9] There are at least eight important hormones that decline with age: 1. human growth hormone (HGH); 2. the sexual hormones: testosterone or oestrogen/progesterone; 3. erythropoietin (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. In line with this, recent experiments show that heterochronic parabiosis, i.e. connecting the circulatory systems of young and old animal, leads to the rejuvenation of the old animal, including restoration of proper stem cell function. Similar experiments show that grafting old muscles into young hosts leads to their complete restoration, whereas grafting young muscles into old hosts does not. These experiments show that aging is mediated by systemic environment, rather than being an intrinsic cell property.[ citation needed ] Clinical trials based on transfusion of young blood were scheduled to begin in 2014. [10] Another intervention that is gaining popularity is epigenetic reprogramming. [11] Through the use of Yamanaka factors, aged cells can revert to a younger state. It has been demonstrated that reprogramming induces a youthful epigenetic state and can restore vision after injury. [12] Only through reprogramming were stochastic epigenetic variations, which accumulate with age, successfully reversed, as demonstrated by a stochastic data-based clock. [13]

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. [14] More recent efforts leverage CRISPR-Cas systems or adeno-associated viruses (AAVs).

Enhanced DNA repair has been proposed as a potential rejuvenation strategy. [15]

Stem cell 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
  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. [16]

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 commonly found throughout history, many fake rejuvenation products that have been shown to be ineffective. Chief among these are powders, sprays, gels, and homeopathic substances that claim to contain growth hormones. Authentic growth hormones are only effective when injected, mainly due to the fact that the 191-amino acid protein is too large to be absorbed through the mucous membranes, and would be broken up in the stomach if swallowed.

The Mprize scientific competition is under way to deliver on the mission of extending healthy human life. It directly accelerates the development of revolutionary new life extension therapies by awarding two cash prizes: one to the research team that breaks the world record for the oldest-ever mouse; and one to the team that develops the most successful late-onset rejuvenation. Current Mprize winner for rejuvenation is Steven Spindler. Caloric restriction (CR), the consumption of fewer calories while avoiding malnutrition, was applied as a robust method of decelerating aging and the development of age-related diseases. [17]

Strategies for engineered negligible senescence

The biomedical gerontologist Aubrey de Grey has initiated a project, strategies for engineered negligible senescence (SENS), to study how to reverse the damage caused by aging. He has proposed seven strategies for what he calls the seven deadly sins of aging: [18]

  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.

In 2009, Aubrey de Grey co-founded the SENS Foundation to expedite progress in the above-listed areas.

Scientific journal

See also

Related Research Articles

Senescence or biological aging is the gradual deterioration of functional characteristics in living organisms. Whole organism senescence involves an increase in death rates and/or a decrease in fecundity with increasing age, at least in the later part of an organism's life cycle. However, the resulting effects of senescence can be delayed. The 1934 discovery that calorie restriction can extend lifespans by 50% in rats, the existence of species having negligible senescence, and the existence of potentially immortal organisms such as members of the genus Hydra have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

<span class="mw-page-title-main">Somatic cell nuclear transfer</span> Method of creating a cloned embryo by replacing the egg nucleus with a body cell nucleus

In genetics and developmental biology, somatic cell nuclear transfer (SCNT) is a laboratory strategy for creating a viable embryo from a body cell and an egg cell. The technique consists of taking a denucleated oocyte and implanting a donor nucleus from a somatic (body) cell. It is used in both therapeutic and reproductive cloning. In 1996, Dolly the sheep became famous for being the first successful case of the reproductive cloning of a mammal. In January 2018, a team of scientists in Shanghai announced the successful cloning of two female crab-eating macaques from foetal nuclei.

Life extension is the concept of extending the human lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled biological limit of around 125 years. Several researchers in the area, along with "life extensionists", "immortalists", or "longevists", postulate that future breakthroughs in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals, and organ replacement will eventually enable humans to have indefinite lifespans through complete rejuvenation to a healthy youthful condition (agerasia). The ethical ramifications, if life extension becomes a possibility, are debated by bioethicists.

<span class="mw-page-title-main">Telomerase</span> Telomere-restoring protein active in the most rapidly dividing cells

Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses retrotransposons to maintain telomeres.

<span class="mw-page-title-main">Germline</span> Population of a multicellular organisms cells that pass on their genetic material to the progeny

In biology and genetics, the germline is the population of a multicellular organism's cells that develop into germ cells. In other words, they are the cells that form gametes, which can come together to form a zygote. They differentiate in the gonads from primordial germ cells into gametogonia, which develop into gametocytes, which develop into the final gametes. This process is known as gametogenesis.

Biological immortality is a state in which the rate of mortality from senescence is stable or decreasing, thus decoupling it from chronological age. Various unicellular and multicellular species, including some vertebrates, achieve this state either throughout their existence or after living long enough. A biologically immortal living being can still die from means other than senescence, such as through injury, poison, disease, predation, lack of available resources, or changes to environment.

Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally, the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by interfering with the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.

<span class="mw-page-title-main">Dyskeratosis congenita</span> Medical condition

Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa, and MDS/AML, but these components do not always occur. DKC is characterized by short telomeres. Some of the manifestations resemble premature ageing and cognitive impairment can be a feature. The disease initially mainly affects the skin, but a major consequence is progressive bone marrow failure which occurs in over 80%, causing early mortality.

In biology, reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development or in cell culture. Such control is also often associated with alternative covalent modifications of histones.

The following outline is provided as an overview of and topical guide to life extension:

<span class="mw-page-title-main">Induced pluripotent stem cell</span> Pluripotent stem cell generated directly from a somatic cell

Induced pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka and Kazutoshi Takahashi in Kyoto, Japan, who together showed in 2006 that the introduction of four specific genes, collectively known as Yamanaka factors, encoding transcription factors could convert somatic cells into pluripotent stem cells. Shinya Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent."

<span class="mw-page-title-main">Telomerase reverse transcriptase</span> Catalytic subunit of the enzyme telomerase

Telomerase reverse transcriptase is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.

The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly or directly.

<span class="mw-page-title-main">Juan Carlos Izpisua Belmonte</span> Spanish biochemist and developmental biologist

Juan Carlos Izpisua Belmonte is a Spanish biochemist and developmental biologist. He is a professor in the Gene Expression Laboratories at the Salk Institute for Biological Studies in La Jolla, California since 1993.

Induced stem cells (iSC) are stem cells derived from somatic, reproductive, pluripotent or other cell types by deliberate epigenetic reprogramming. They are classified as either totipotent (iTC), pluripotent (iPSC) or progenitor or unipotent – (iUSC) according to their developmental potential and degree of dedifferentiation. Progenitors are obtained by so-called direct reprogramming or directed differentiation and are also called induced somatic stem cells.

An epigenetic clock is a biochemical test that can be used to measure age. The test is based on DNA methylation levels, measuring the accumulation of methyl groups to one's DNA molecules.

<span class="mw-page-title-main">Helen Blau</span> American biochemist

Helen Blau is a cell biologist and stem cell researcher famous for her work on muscle diseases, regeneration and aging. She is the Donald E. and Delia B. Baxter Foundation Professor and the Director of the Baxter Laboratory for Stem Cell Biology at Stanford University. Blau is known for overturning the prevailing view that once a cell assumes a certain specialty in the body — or differentiated state —such as a skin or liver cell, it cannot be changed. Her research established that the fate of mammalian cells can be altered. Her finding that specialized cells can be triggered to turn on genetic programs characteristic of other differentiated states provided early evidence that mammalian cellular reprogramming was possible and opened the door to the use of reprogramming in stem cell biology. Her work set the stage for the development of induced pluripotent stem cells and associated stem cell therapies.

<span class="mw-page-title-main">María Blasco Marhuenda</span> Spanish scientist

María Antonia Blasco Marhuenda, known as María Blasco, is a Spanish molecular biologist. She is the current director of the Spanish National Cancer Research Centre.

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. The hallmarks of aging are the types of biochemical changes that occur in all organisms that experience biological aging and lead to a progressive loss of physiological integrity, impaired function and, eventually, death. They were first listed in a landmark paper in 2013 to conceptualize the essence of biological aging and its underlying mechanisms.

This timeline lists notable events in the history of research into senescence or biological aging, including the research and development of life extension methods, brain aging delay methods and rejuvenation.

References

  1. ↑ De Grey AD (2004). "Welcome to Rejuvenation Research". Rejuvenation Research . 7: 1–2. doi:10.1089/154916804323105017.
  2. ↑ Shapin S, Martyn C (2000). "How to live forever: lessons of history". BMJ. 321 (7276): 1580–2. doi:10.1136/bmj.321.7276.1580. PMC   1119261 . PMID   11124187.
  3. ↑ Common, Laura. (April 25, 2000) The Medical Post Great balls of fire: from prehistory, men have tried implants and extracts from macho animals to cure impotence, but it was only relatively recently that they began to understand why they did so.
  4. ↑ Grossman R (31 March 1985). "Lost lake shore drive: Mourning an era; Mansions of rich and famous yield to giant condos". Chicago Tribune .
  5. ↑ Jones, David. (December 11, 1986) The Times Christmas Books: Believe it or not - Adam and Eve to bent spoons / Review of books on beliefs.
  6. ↑ Chaisinthop N (2013). "What is Fresh Cell Therapy?" (PDF). Archived from the original (PDF) on 22 February 2016.
  7. ↑ Robyn MP, Newman AP, Amato M, Walawander M, Kothe C, Nerone JD, et al. (October 2015). "Q Fever Outbreak Among Travelers to Germany Who Received Live Cell Therapy--United States and Canada, 2014". MMWR. Morbidity and Mortality Weekly Report. 64 (38): 1071–3. doi: 10.15585/mmwr.mm6438a3 . PMID   26421460.
  8. ↑ "Dr. Janson-Müller: Hintergründe".
  9. ↑ Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC, et al. (January 2011). "Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice". Nature. 469 (7328): 102–6. Bibcode:2011Natur.469..102J. doi:10.1038/nature09603. PMC   3057569 . PMID   21113150.
  10. ↑ Thomson H (August 20, 2014). "Young blood to be used in ultimate rejuvenation trial". New Scientist.
  11. ↑ de Lima Camillo LP, Quinlan RB (April 2021). "A ride through the epigenetic landscape: aging reversal by reprogramming". GeroScience. 43 (2): 463–485. doi: 10.1007/s11357-021-00358-6 . PMC   8110674 . PMID   33825176.
  12. ↑ Lu, Yuancheng; Brommer, Benedikt; Tian, Xiao; Krishnan, Anitha; Meer, Margarita; Wang, Chen; Vera, Daniel L.; Zeng, Qiurui; Yu, Doudou; Bonkowski, Michael S.; Yang, Jae-Hyun; Zhou, Songlin; Hoffmann, Emma M.; Karg, Margarete M.; Schultz, Michael B. (December 2020). "Reprogramming to recover youthful epigenetic information and restore vision". Nature. 588 (7836): 124–129. doi:10.1038/s41586-020-2975-4. ISSN   1476-4687. PMC   7752134 . PMID   33268865.
  13. ↑ Meyer, David H.; Schumacher, Björn (2024-05-09). "Aging clocks based on accumulating stochastic variation". Nature Aging: 1–15. doi:10.1038/s43587-024-00619-x. ISSN   2662-8465.
  14. ↑ Kaiser J (December 2005). "Gene therapy. Putting the fingers on gene repair". Science. 310 (5756): 1894–6. doi: 10.1126/science.310.5756.1894 . PMID   16373552.
  15. ↑ Chen Y, Geng A, Zhang W, Qian Z, Wan X, Jiang Y, Mao Z (December 2020). "Fight to the bitter end: DNA repair and aging". Ageing Research Reviews. 64: 101154. doi:10.1016/j.arr.2020.101154. PMID   32977059. S2CID   221824975.
  16. ↑ Brockes JP, Kumar A (December 2005). "Appendage regeneration in adult vertebrates and implications for regenerative medicine". Science. 310 (5756): 1919–23. Bibcode:2005Sci...310.1919B. doi: 10.1126/science.1115200 . PMID   16373567. S2CID   22810456.
  17. ↑ Dhahbi JM, Kim HJ, Mote PL, Beaver RJ, Spindler SR (April 2004). "Temporal linkage between the phenotypic and genomic responses to caloric restriction". Proceedings of the National Academy of Sciences of the United States of America. 101 (15): 5524–9. Bibcode:2004PNAS..101.5524D. doi: 10.1073/pnas.0305300101 . PMC   397416 . PMID   15044709.
  18. ↑ de Grey A, Rae M (September 2007). Ending Aging: The Rejuvenation Breakthroughs that Could Reverse Human Aging in Our Lifetime. New York, NY: St. Martin's Press. pp.  416. ISBN   978-0-312-36706-0.
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