Rejuvenation is a medical discipline focused on the practical reversal of the aging process. Rejuvenation is distinct from life extension. Life extension strategies often study the causes of aging and try to oppose those causes 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 Supernatural phenomena or entities are those beyond the Scientific law, laws of nature. The term is derived from Medieval Latin , from Latin 'above, beyond, outside of' + 'nature'. Although the corollary term "nature" has had multiple meanin ...

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 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 Heaven, or the Heavens, is a common Religious cosmology, religious cosmological or supernatural place where beings such as deity, deities, angels, souls, saints, or Veneration of the dead, venerated ancestors are said to originate, be throne, ...

. 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 Florida ( ; ) is a U.S. state, state in the Southeastern United States, Southeastern region of the United States. It borders the Gulf of Mexico to the west, Alabama to the northwest, Georgia (U.S. state), Georgia to the north, the Atlantic ...

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 Philosophy ('love of wisdom' in Ancient Greek) is a systematic study of general and fundamental questions concerning topics like existence, reason, knowledge, Value (ethics and social sciences), value, mind, and language. It is a rational an ...

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

potion A potion is a liquid "that contains medicine, poison, or something that is supposed to have magic powers." It derives from the Latin word ''potio'' which refers to a drink or the act of drinking. The term philtre is also used, often specifica ...

s 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

child A child () is a human being between the stages of childbirth, birth and puberty, or between the Development of the human body, developmental period of infancy and puberty. The term may also refer to an unborn human being. In English-speaking ...

ren (sometimes literally sleeping, not necessarily having sex), 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 The scientific method is an Empirical evidence, empirical method for acquiring knowledge that has been referred to while doing science since at least the 17th century. Historically, it was developed through the centuries from the ancient and ...

and so to the medical advances of today. 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 Algiers is the capital city of Algeria as well as the capital of the Algiers Province; it extends over many Communes of Algeria, communes without having its own separate governing body. With 2,988,145 residents in 2008Census 14 April 2008: Offi ...

. Noteworthy people who had the surgery included Harold McCormick, chairman of the board of International Harvester Company, and the aging premier of

Turkey Turkey, officially the Republic of Türkiye, is a country mainly located in Anatolia in West Asia, with a relatively small part called East Thrace in Southeast Europe. It borders the Black Sea to the north; Georgia (country), Georgia, Armen ...

. 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 An organism is any life, living thing that functions as an individual. Such a definition raises more problems than it solves, not least because the concept of an individual is also difficult. Many criteria, few of them widely accepted, have be ...

, ultimately leads to its

death Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sh ...

. 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 A laboratory (; ; colloquially lab) is a facility that provides controlled conditions in which scientific or technological research, experiments, and measurement may be performed. Laboratories are found in a variety of settings such as schools ...

animals, thereby achieving life extension. A few experimental methods such as replacing

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

s 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. 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 Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production ( erythropoiesis) in th ...

(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. Clinical trials based on transfusion of young blood were scheduled to begin in 2014. Another intervention that is gaining popularity is epigenetic reprogramming. 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. Only through reprogramming were stochastic epigenetic variations, which accumulate with age, successfully reversed, as demonstrated by a stochastic data-based clock. Most attempts at genetic repair have traditionally involved the use of a retrovirus to insert a new

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

into a random position on a

chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...

. But by attaching zinc fingers (which determine where

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

s bind) to

endonuclease In molecular biology, endonucleases are enzymes that cleave the phosphodiester bond within a polynucleotide chain (namely DNA or RNA). Some, such as deoxyribonuclease I, cut DNA relatively nonspecifically (with regard to sequence), while man ...

s (which break DNA strands),

homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...

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

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s, to correct those mutations in laboratory dishes using zinc finger endonucleases and to transplant the stem cells back into the patients. More recent efforts leverage CRISPR-Cas systems or adeno-associated viruses (AAVs). Enhanced DNA repair has been proposed as a potential rejuvenation strategy. Stem cell regenerative medicine uses three different strategies: # Implantation of stem cells from

culture Culture ( ) is a concept that encompasses the social behavior, institutions, and Social norm, norms found in human societies, as well as the knowledge, beliefs, arts, laws, Social norm, customs, capabilities, Attitude (psychology), attitudes ...

into an existing tissue structure # Implantation of stem cells into a tissue scaffold that guides restoration # 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. 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 The abdomen (colloquially called the gut, belly, tummy, midriff, tucky, or stomach) is the front part of the torso between the thorax (chest) and pelvis in humans and in other vertebrates. The area occupied by the abdomen is called the abdominal ...

breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...

s, 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. In 2020, scientists reported the reversion of ageing in human cells through nuclear reprogramming to pluripotency. Such process included resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes and restoration of youthful regenerative response to aged, human muscle stem cells, without abolishing cellular identity.

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: # Cell loss can be repaired (reversed) just by suitable

exercise Exercise or workout is physical activity that enhances or maintains fitness and overall health. It is performed for various reasons, including weight loss or maintenance, to aid growth and improve strength, develop muscles and the cardio ...

in the case of

muscle Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...

. For other tissues it needs various growth factors to stimulate cell division, or in some cases it needs stem cells. # Senescent cells can be removed by activating the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

against them. Or they can be destroyed by gene therapy to introduce "suicide

s" that only kill senescent cells. #

Protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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. #

Extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

garbage (like amyloid) can be eliminated by

vaccination Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulating ...

that gets immune cells to "eat" the garbage. # For intracellular junk we need to introduce new

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s, possibly enzymes from soil

bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

, that can degrade the junk ( lipofuscin) that our own natural enzymes cannot degrade. # 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 The cell nucleus (; : nuclei) is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have #Anucleated_cells, ...

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

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s would then be imported into the mitochondria. # For

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

(the most lethal consequence of mutations) the strategy is to use gene therapy to delete the

s 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

* '' Rejuvenation Research'' Editor: Aubrey de Grey. Publisher: Mary Ann Liebert, Inc. ISSN 1549-1684 – Published Bimonthly.

References

External links