Life extension

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 limit of 125 years.[1]

For other uses, see Life extension (disambiguation).

Several researchers in the area, along with "life extensionists", "immortalists" or "longevists" (those who wish to achieve longer lives themselves), postulate that future breakthroughs in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals and organ replacement (such as with artificial organs or xenotransplantations) will eventually enable humans to have indefinite lifespans (agerasia[2]) through complete rejuvenation to a healthy youthful condition. The ethical ramifications, if life extension becomes a possibility, are debated by bioethicists.

The sale of purported anti-aging products such as supplements and hormone replacement is a lucrative global industry. For example, the industry that promotes the use of hormones as a treatment for consumers to slow or reverse the aging process in the US market generated about $50 billion of revenue a year in 2009.[3] The use of such hormone products, however, has not been proven to be effective or safe.[3][4][5][6]

Average and maximum lifespan
Main article: Senescence

During the process of aging, an organism accumulates damage to its macromolecules, cells, tissues, and organs. Specifically, aging is characterized as and thought to be caused by "genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication."[7] Oxidation damage to cellular contents caused by free radicals is believed to contribute to aging as well.[8][9]

The longest documented human lifespan is 122 years 164 days, the case of Jeanne Calment who according to records was born in 1875 and died in 1997, whereas the maximum lifespan of a wildtype mouse, commonly used as a model in research on aging, is about three years.[10] Genetic differences between humans and mice that may account for these different aging rates include differences in efficiency of DNA repair, antioxidant defenses, energy metabolism, proteostasis maintenance, and recycling mechanisms such as autophagy.[11]

The average lifespan in a population is lowered by infant and child mortality, which are frequently linked to infectious diseases or nutrition problems. Later in life, vulnerability to accidents and age-related chronic disease such as cancer or cardiovascular disease play an increasing role in mortality. Extension of expected lifespan can often be achieved by access to improved medical care, vaccinations, good diet, exercise and avoidance of hazards such as smoking.

Maximum lifespan is determined by the rate of aging for a species inherent in its genes and by environmental factors. Widely recognized methods of extending maximum lifespan in model organisms such as nematodes, fruit flies, and mice include caloric restriction, gene manipulation, and administration of pharmaceuticals.[12] Another technique uses evolutionary pressures such as breeding from only older members or altering levels of extrinsic mortality.[13][14] Some animals such as hydra, planarian flatworms, and certain sponges, corals, and jellyfish do not die of old age and exhibit potential immortality.[15][16][17][18]

Strategies
See also: Ageing § Prevention and delay

Vitamins and antioxidants

The free-radical theory of aging suggests that antioxidant supplements might extend human life. Reviews, however, have found that use of vitamin A (as β-carotene) and vitamin E supplements possibly can increase mortality.[19][20] Other reviews have found no relationship between vitamin E and other vitamins with mortality.[21]

Dietary restriction

In some studies calorie restriction has been shown to extend the life of mice, yeast, and rhesus monkeys.[22][23] However, a more recent study did not find calorie restriction to improve survival in rhesus monkeys.[24] In humans the long-term health effects of moderate caloric restriction with sufficient nutrients are unknown.[25]

According to two scientific reviews published in 2021, accumulating data suggests dietary restriction (DR) – mainly intermittent fasting and caloric restriction – results in many of the same beneficial changes in adult humans as in studied organisms, potentially increasing health- and lifespan beyond[26] the benefits of healthy body weight.[26][27] Which protocols of and combinations (e.g. see caloric restriction mimetic and AMPK) with DR are effective or most effective in humans is largely unknown and is being actively researched. A geroscience field of "precision nutrigeroscience" is proposed that also considers the potential need for adjustments of nutritional interventions per individual (e.g. due to differences in genetics and age).[27] Intermittent fasting refers to periods with intervals during which no food but only e.g. water and tea/coffee are ingested – such as a period of daily time-restricted eating with a window of 8 to 12 hours for any caloric intake – and could be combined with overall caloric restriction and variants of the Mediterranean diet which usually has benefits of long-term cardiovascular health and longevity.[28]

During periods of caloric restriction, higher protein intakes "may be required to maximize muscle retention in lean, resistance-trained subjects"[29] and "resistance training (RT) can attenuate muscle loss during caloric restriction"[30] with strength training also generally being associated with a "10–17% lower risk of all-cause mortality, cardiovascular disease (CVD), total cancer, diabetes and lung cancer".[31]

Mechanistically, research to date has identified various nutrient sensors involved in the beneficial effects of caloric restriction as well as methionine-reduction/restriction including notably AMPK[32] (see also: mTOR inhibitors), mTOR, insulin-related pathways, sirtuins,[33] NAD+,[34] NFkB, and FOXO and, partly by extension, processes such as autophagy.[35][36][37][26]

Healthy diet

Research suggests that increasing adherence to Mediterranean diet patterns is associated with a reduction in total and cause-specific mortality, extending health- and lifespan.[38][39][37] Research is identifying the key beneficial components of the Mediterranean diet.[40] It shares various characteristics with the similarly beneficial Okinawa diet.[41] Potential anti-aging mechanisms of various nutrients are not yet understood.[42]

Studies suggest dietary changes are a major cause of national relative rises in life-span.[43]

Microbiome

Mechanistically, research suggests that the gut microbiome, which varies per person and changes throughout lifespan, is also involved in the beneficial effects, due to which various diet supplementations with prebiotics, various diverse probiotics and synbiotics, and fecal microbiota transplantation are being investigated for life extension,[44][45] mainly for prolonging healthspan,[46][47] with many important questions being unresolved.[48]

Optimal diet
Expected life years gained for 20-year-olds in U.S. who change from a typical Western diet to an, according to an integrative study, "optimized diet" (changes indicated on the left in gram).[49]

Approaches to develop optimal diets for health- and lifespan include:

  • modifying or further particularizing the Mediterranean diet as the baseline such as via (additional) increase in plant-based (but protein-rich) foods alongside additional restriction of meat intake and regular moderate consumption of green tea or coffee while ensuring adequate calcium intake[50][51] or via (additional) increase in omega-3-containing seafoods[40] or via adding various foods thought to be healthy (e.g. due to results about various mechanistic effects) to the regular dietary consumption patterns.[52]
  • inferring an optimal diet indiscriminately for all levels and forms of physical activities and age and other person-characteristics by integrating the available meta-analyses and data from mostly observational studies. This has been done for a tool and visualizations that show populations' relative general life extension potentials of different food groups, suggesting i.a. that a 20-years old male in Europe who switches to the "optimal diet" could gain a mean of ~13.7 years of life and a 60-years old female in the U.S. switching to the "optimal diet" could gain a mean of ~8.0 years of life. It found the largest gains would be made by eating more legumes, whole grains, and nuts, and less red meat and processed meat. The optimal diet contains no consumption of sugar-sweetened beverages (moving from "typical Western diet" of 500 g/day to 0 g/day). The study notes of uncertainty in "the effect of eggs, white meat, and oils, individual variation in protective and risk factors, uncertainties for future development of medical treatments; and changes in lifestyle".[49]

Senolytics and senomorphics
This section is an excerpt from Senolytic.[edit]
A senolytic (from the words senescence and -lytic, "destroying") is among a class of small molecules under basic research to determine if they can selectively induce death of senescent cells and improve health in humans.[53] A goal of this research is to discover or develop agents to delay, prevent, alleviate, or reverse age-related diseases.[54][55] A related concept is "senostatic", which means to suppress senescence.

Senolytics eliminate senescent cells whereas senomorphics – with candidates such as Apigenin, Everolimus and Rapamycin – modulate properties of senescent cells without eliminating them, suppressing phenotypes of senescence, including the SASP.[56][57]

Hormone treatment

The anti-aging industry offers several hormone therapies. Some of these have been criticized for possible dangers and a lack of proven effect. For example, the American Medical Association has been critical of some anti-aging hormone therapies.[3]

While growth hormone (GH) decreases with age, the evidence for use of growth hormone as an anti-aging therapy is mixed and based mostly on animal studies. There are mixed reports that GH or IGF-1 modulates the aging process in humans and about whether the direction of its effect is positive or negative.[58]

Societal strategies
See also: Screening (medicine), Metascience, Medical research, and § Scientific research

Collectively, addressing common causes of death could extend lifespans of populations and humanity overall. For instance, a 2020 study indicates that the global mean loss of life expectancy (LLE) from air pollution in 2015 was 2.9 years, substantially more than, for example, 0.3 years from all forms of direct violence, albeit a significant fraction of the LLE is considered to be unavoidable.[59]

History
Further information: Timeline of senescence research

The extension of life has been a desire of humanity and a mainstay motif in the history of scientific pursuits and ideas throughout history, from the Sumerian Epic of Gilgamesh and the Egyptian Smith medical papyrus, all the way through the Taoists, Ayurveda practitioners, alchemists, hygienists such as Luigi Cornaro, Johann Cohausen and Christoph Wilhelm Hufeland, and philosophers such as Francis Bacon, René Descartes, Benjamin Franklin and Nicolas Condorcet. However, the beginning of the modern period in this endeavor can be traced to the end of the 19th – beginning of the 20th century, to the so-called "fin-de-siècle" (end of the century) period, denoted as an "end of an epoch" and characterized by the rise of scientific optimism and therapeutic activism, entailing the pursuit of life extension (or life-extensionism). Among the foremost researchers of life extension at this period were the Nobel Prize winning biologist Elie Metchnikoff (1845-1916) -- the author of the cell theory of immunity and vice director of Institut Pasteur in Paris, and Charles-Édouard Brown-Séquard (1817-1894) -- the president of the French Biological Society and one of the founders of modern endocrinology.[60]

Sociologist James Hughes claims that science has been tied to a cultural narrative of conquering death since the Age of Enlightenment. He cites Francis Bacon (1561–1626) as an advocate of using science and reason to extend human life, noting Bacon's novel New Atlantis, wherein scientists worked toward delaying aging and prolonging life. Robert Boyle (1627–1691), founding member of the Royal Society, also hoped that science would make substantial progress with life extension, according to Hughes, and proposed such experiments as "to replace the blood of the old with the blood of the young". Biologist Alexis Carrel (1873–1944) was inspired by a belief in indefinite human lifespan that he developed after experimenting with cells, says Hughes.[61]

Regulatory and legal struggles between the Food and Drug Administration (FDA) and the Life Extension organization included seizure of merchandise and court action.[62] In 1991, Saul Kent and Bill Faloon, the principals of the organization, were jailed for four hours and were released on $850,000 bond each.[63] After 11 years of legal battles, Kent and Faloon convinced the US Attorney's Office to dismiss all criminal indictments brought against them by the FDA.[64]

In 2003, Doubleday published "The Immortal Cell: One Scientist's Quest to Solve the Mystery of Human Aging," by Michael D. West. West emphasised the potential role of embryonic stem cells in life extension.[65]

Other modern life extensionists include writer Gennady Stolyarov, who insists that death is "the enemy of us all, to be fought with medicine, science, and technology";[66] transhumanist philosopher Zoltan Istvan, who proposes that the "transhumanist must safeguard one's own existence above all else";[67] futurist George Dvorsky, who considers aging to be a problem that desperately needs to be solved;[68] and recording artist Steve Aoki, who has been called "one of the most prolific campaigners for life extension".[69]

Scientific research

In 1991, the American Academy of Anti-Aging Medicine (A4M) was formed. The American Board of Medical Specialties recognizes neither anti-aging medicine nor the A4M's professional standing.[70]

In 2003, Aubrey de Grey and David Gobel formed the Methuselah Foundation, which gives financial grants to anti-aging research projects. In 2009, de Grey and several others founded the SENS Research Foundation, a California-based scientific research organization which conducts research into aging and funds other anti-aging research projects at various universities.[71] In 2013, Google announced Calico, a new company based in San Francisco that will harness new technologies to increase scientific understanding of the biology of aging.[72] It is led by Arthur D. Levinson,[73] and its research team includes scientists such as Hal V. Barron, David Botstein, and Cynthia Kenyon. In 2014, biologist Craig Venter founded Human Longevity Inc., a company dedicated to scientific research to end aging through genomics and cell therapy. They received funding with the goal of compiling a comprehensive human genotype, microbiome, and phenotype database.[74]

Aside from private initiatives, aging research is being conducted in university laboratories, and includes universities such as Harvard and UCLA. University researchers have made a number of breakthroughs in extending the lives of mice and insects by reversing certain aspects of aging.[75][76][77][78]

Ethics and politics

Scientific controversy

Some critics dispute the portrayal of aging as a disease. For example, Leonard Hayflick, who determined that fibroblasts are limited to around 50 cell divisions, reasons that aging is an unavoidable consequence of entropy. Hayflick and fellow biogerontologists Jay Olshansky and Bruce Carnes have strongly criticized the anti-aging industry in response to what they see as unscrupulous profiteering from the sale of unproven anti-aging supplements.[5]

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