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Thursday, August 20, 2026

Life extension

From Wikipedia, the free encyclopedia

Life extension is the concept of extending the human lifespan, either through incremental improvements in medicine or through radical increases in maximum lifespan beyond its generally-settled biological limit of around 125 years. This field of study has been explored by numerous researchers and advocates, including "life extensionists", "immortalists", and "longevists" (those who aspire to achieve prolonged lifespans themselves). These researchers and advocates hypothesize that future advancements in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals, and organ replacement (such as through artificial organs or xenotransplantations) will eventually enable humans to have indefinite lifespans through complete rejuvenation to a state of optimal health and youth (agerasia). The ethical implications of life extension are a subject of discourse among bioethicists.

The sale of purported anti-aging products, such as supplements and hormone replacement therapy, 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. The use of such hormone products has not been proven to be effective or safe. Similarly, a variety of apps make claims to assist in extending the life of their users, or predicting their lifespans.

Average life expectancy and lifespan

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." Oxidation damage to cellular contents caused by free radicals is believed to contribute to aging as well.

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. 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.

The average life expectancy 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 life expectancy and 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. Another technique uses evolutionary pressures such as breeding from only older members or altering levels of extrinsic mortality. Some animals such as hydra, planarian flatworms, and certain sponges, corals, and jellyfish do not die of old age and exhibit potential immortality.

History

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.

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.

Contemporary

Regulatory and legal struggles between the Food and Drug Administration (FDA) and the Life Extension organization included seizure of merchandise and court action. 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. 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.

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.

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"; transhumanist philosopher Zoltan Istvan, who proposes that the "transhumanist must safeguard one's own existence above all else"; futurist George Dvorsky, who considers aging to be a problem that desperately needs to be solved; and recording artist Steve Aoki, who has been called "one of the most prolific campaigners for life extension".

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.

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. 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. It is led by Arthur D. Levinson, 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.

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.

Research

Theoretically, extension of maximum lifespan in humans could be achieved by reducing the rate of aging damage by periodic replacement of damaged tissues, molecular repair or rejuvenation of deteriorated cells and tissues, reversal of harmful epigenetic changes, or the enhancement of enzyme telomerase activity.

Research geared towards life extension strategies in various organisms is currently under way at a number of academic and private institutions. Since 2009, investigators have found ways to increase the lifespan of nematode worms and yeast by 10-fold; the record in nematodes was achieved through genetic engineering and the extension in yeast by a combination of genetic engineering and caloric restriction. A 2009 review of longevity research noted: "Extrapolation from worms to mammals is risky at best, and it cannot be assumed that interventions will result in comparable life extension factors. Longevity gains from dietary restriction, or from mutations studied previously, yield smaller benefits to Drosophila than to nematodes, and smaller still to mammals. This is not unexpected, since mammals have evolved to live many times the worm's lifespan, and humans live nearly twice as long as the next longest-lived primate. From an evolutionary perspective, mammals and their ancestors have already undergone several hundred million years of natural selection favoring traits that could directly or indirectly favor increased longevity, and may thus have already settled on gene sequences that promote lifespan. Moreover, the very notion of a "life-extension factor" that could apply across taxa presumes a linear response rarely seen in biology."

Anti-aging/life-extension drugs

There are numerous chemicals intended to slow the aging process under study in animal models. One type of research is related to the observed effects of a calorie restriction (CR) diet, which has been shown to extend lifespan in some animals. Based on that research, there have been attempts to develop drugs that will have the same effect on the aging process as a CR diet, which are known as caloric restriction mimetic drugs, such as rapamycin and metformin.

Sirtuin activating polyphenols, such as resveratrol and pterostilbene, and flavonoids, such as quercetin and fisetin, as well as oleic acid are dietary supplements that have also been studied in this context. Other common supplements with less clear biological pathways to target aging include lipoic acidsenolytics, and coenzyme Q10.

While agents such as these have some limited laboratory evidence of efficacy in animals, there are no studies to date in humans for drugs that may promote life extension, mainly because research investment remains at a low level, and regulatory standards are high. Aging is not recognized as a preventable condition by governments, indicating there is no clear pathway to approval of anti-aging medications. Further, anti-aging drug candidates are under constant review by regulatory authorities like the US Food and Drug Administration, which stated in 2023 that "no medication has been proven to slow or reverse the aging process."

LDL-C lowering drugs such as statins and PCSK9 inhibitors present with some of the most promising candidates for increasing lifespan since there is substantial randomized genetic and clinical evidence that reduced risk of atherosclerotic cardiovascular disease via reducing LDL-C would yield a net gain in lifespan.

Nanotechnology

Future advances in nanomedicine could give rise to life extension through the repair of many processes thought to be responsible for aging. K. Eric Drexler, one of the founders of nanotechnology, postulated cell repair machines, including ones operating within cells and utilizing as yet hypothetical molecular computers, in his 1986 book Engines of Creation. Raymond Kurzweil, a futurist and transhumanist, stated in his book The Singularity Is Near that he believes that advanced medical nanorobotics could completely remedy the effects of aging by 2030. According to Richard Feynman, it was his former graduate student and collaborator Albert Hibbs who originally suggested to him (circa 1959) the idea of a medical use for Feynman's theoretical nanomachines (see biological machine). Hibbs suggested that certain repair machines might one day be reduced in size to the point that it would, in theory, be possible to (as Feynman put it) "swallow the doctor". The idea was incorporated into Feynman's 1959 essay There's Plenty of Room at the Bottom.

Cyborgs

The replacement of biological organs, which are susceptible to diseases, with mechanical ones has the potential to extend life. This is the goal of the 2045 Initiative.

Cryonics

Cryonics is the low-temperature freezing (usually at −196 °C or −320.8 °F or 77.1 K) of a human corpse, with the hope that resuscitation may be possible in the future. It is regarded with skepticism within the mainstream scientific community and has been characterized as quackery.

Strategies for engineered negligible senescence

Another proposed life extension technology aims to combine existing and predicted future biochemical and genetic techniques. SENS proposes that rejuvenation may be obtained by removing aging damage via the use of stem cells and tissue engineering, telomere-lengthening machinery, allotopic expression of mitochondrial proteins, targeted ablation of cells, immunotherapeutic clearance, and novel lysosomal hydrolases.

While some biogerontologists find these ideas "worthy of discussion", others contend that the alleged benefits are too speculative given the current state of technology, referring to it as "fantasy rather than science".

Genetic editing

Genome editing, in which nucleic acid polymers are delivered as a drug and are either expressed as proteins, interfere with the expression of proteins, or correct genetic mutations, has been proposed as a future strategy to prevent aging.

CRISPR/Cas9

CRISPR/Cas9 edits genes by precisely cutting DNA and then harnessing natural DNA repair processes to modify the gene in the desired manner. The system has two components: the Cas9 enzyme and a guide RNA. A large array of genetic modifications have been found to increase lifespan in model organisms such as yeast, nematode worms, fruit flies, and mice. As of 2013, the longest extension of life caused by a single gene manipulation was roughly 50% in mice and 10-fold in nematode worms.

"Healthspan, parental lifespan, and longevity are highly genetically correlated."

In July 2020 scientists, using public biological data on 1.75 m people with known lifespans overall, identify 10 genomic loci which appear to intrinsically influence healthspan, lifespan, and longevity – of which half have not been reported previously at genome-wide significance and most being associated with cardiovascular disease – and identify haem metabolism as a promising candidate for further research within the field. Their study suggests that high levels of iron in the blood likely reduce, and genes involved in metabolising iron likely increase healthy years of life in humans. The same month other scientists report that yeast cells of the same genetic material and within the same environment age in two distinct ways, describe a biomolecular mechanism that can determine which process dominates during aging and genetically engineer a novel aging route with substantially extended lifespan.

Fooling genes

In The Selfish Gene, Richard Dawkins describes an approach to life-extension that involves "fooling genes" into thinking the body is young.[76] Dawkins attributes inspiration for this idea to Peter Medawar. The basic idea is that our bodies are composed of genes that activate throughout our lifetimes, some when we are young and others when we are older. Presumably, these genes are activated by environmental factors, and the changes caused by these genes activating can be lethal. It is a statistical certainty that we possess more lethal genes that activate in later life than in early life. Therefore, to extend life, we should be able to prevent these genes from switching on, and we should be able to do so by "identifying changes in the internal chemical environment of a body that take place during aging... and by simulating the superficial chemical properties of a young body".

Cloning and body part replacement

Some life extensionists suggest that therapeutic cloning and stem cell research could one day provide a way to generate cells, body parts, or even entire bodies (generally referred to as reproductive cloning) that would be genetically identical to a prospective patient. In 2008, the US Department of Defense announced a program to research the possibility of growing human body parts on mice. Complex biological structures, such as mammalian joints and limbs, have not yet been replicated. Dog and primate brain transplantation experiments were conducted in the mid-20th century but failed due to rejection and the inability to restore nerve connections. As of 2006, the implantation of bio-engineered bladders grown from patients' own cells has proven to be a viable treatment for bladder disease. Proponents of body part replacement and cloning contend that the required biotechnologies are likely to appear earlier than other life-extension technologies.

The use of human stem cells, particularly embryonic stem cells, is controversial. Opponents' objections generally are based on interpretations of religious teachings or ethical considerations. Proponents of stem cell research point out that cells are routinely formed and destroyed in a variety of contexts. Use of stem cells taken from the umbilical cord or parts of the adult body may not provoke controversy.

The controversies over cloning are similar, except general public opinion in most countries stands in opposition to reproductive cloning. Some proponents of therapeutic cloning predict the production of whole bodies, lacking consciousness, for eventual brain transplantation.

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.

Consumer motivations

Research by Sobh and Martin (2011) suggests that people buy anti-aging products to obtain a hoped-for self (e.g., keeping a youthful skin) or to avoid a feared-self (e.g., looking old). The research shows that when consumers pursue a hoped-for self, it is expectations of success that most strongly drive their motivation to use the product. The research also shows why doing badly when trying to avoid a feared self is more motivating than doing well. When product use is seen to fail it is more motivating than success when consumers seek to avoid a feared-self.

Political parties

Though many scientists state that life extension and radical life extension are possible, there are still no international or national programs focused on radical life extension. There are political forces working both for and against life extension. By 2012, in Russia, the United States, Israel, and the Netherlands, the Longevity political parties started. They aimed to provide political support to radical life extension research and technologies, and ensure the fastest possible and at the same time soft transition of society to the next step – life without aging and with radical life extension, and to provide access to such technologies to most currently living people.

Political leaders

General Secretary of the Chinese Communist Party Xi Jinping and President of Russia Vladimir Putin discussed organ transplants and "immortality" during the 2025 China Victory Day Parade. This conversation is caught recorded by China Central Television's public broadcast. During the conversation, Putin spoke about biotechnology and "human organs will continue to be transplanted, and people will became younger and younger". Xi responded Putin, talking about how people predicted that life expectancy can reach up to 150 years and how 70 years old still is quite young compared to the past. At the press conference during the evening, Putin clarified to Russian media that he and Xi did discuss about the topic of human lifespan.

Silicon Valley

Some tech innovators and Silicon Valley entrepreneurs have invested heavily into anti-aging research. This includes Jeff Bezos (founder of Amazon), Larry Ellison (founder of Oracle), Peter Thiel (former PayPal CEO), Larry Page (co-founder of Google), Peter DiamandisSam Altman (CEO of OpenAI, invested in Retro Biosciences), Brian Armstrong (founder of Coinbase and NewLimit), and Bryan Johnson (Founder of Kernel).

Commentators

Leon Kass (chairman of the US President's Council on Bioethics from 2001 to 2005) has questioned whether potential exacerbation of overpopulation problems would make life extension unethical. He states his opposition to life extension with the words:

"simply to covet a prolonged life span for ourselves is both a sign and a cause of our failure to open ourselves to procreation and to any higher purpose ... [The] desire to prolong youthfulness is not only a childish desire to eat one's life and keep it; it is also an expression of a childish and narcissistic wish incompatible with devotion to posterity."

John Harris, former editor-in-chief of the Journal of Medical Ethics, argues that as long as life is worth living, according to the person himself, we have a powerful moral imperative to save the life and thus to develop and offer life extension therapies to those who want them.

Transhumanist philosopher Nick Bostrom has argued that any technological advances in life extension must be equitably distributed and not restricted to a privileged few. In an extended metaphor entitled "The Fable of the Dragon-Tyrant", Bostrom envisions death as a monstrous dragon who demands human sacrifices. In the fable, after a lengthy debate between those who believe the dragon is a fact of life and those who believe the dragon can and should be destroyed, the dragon is finally killed. Bostrom argues that political inaction allowed many preventable human deaths to occur.

Overpopulation concerns

Controversy about life extension is due to fear of overpopulation and possible effects on society. Biogerontologist Aubrey De Grey counters the overpopulation critique by pointing out that the therapy could postpone or eliminate menopause, allowing women to space out their pregnancies over more years and thus decreasing the yearly population growth rate. Moreover, the philosopher and futurist Max More argues that, given that the worldwide population growth rate is slowing down and is projected to eventually stabilize and begin falling, superlongevity would be unlikely to contribute to overpopulation.

Opinion polls

A Spring 2013 Pew Research poll in the United States found that 38% of Americans would want life extension treatments, and 56% would reject it. However, it also found that 68% believed most people would want it and that only 4% consider an "ideal lifespan" to be more than 120 years. The median "ideal lifespan" was 91 years of age and the majority of the public (63%) viewed medical advances aimed at prolonging life as generally good. 41% of Americans believed that radical life extension (RLE) would be good for society, while 51% said they believed it would be bad for society. One possibility for why 56% of Americans claim they would reject life extension treatments may be due to the cultural perception that living longer would result in a longer period of decrepitude, and that the elderly in our current society are unhealthy.

Religious people are no more likely to oppose life extension than the unaffiliated, though some variation exists between religious denominations.

Aging as a disease

Most mainstream medical organizations and practitioners do not consider aging to be a disease. Biologist David Sinclair says: "I don't see aging as a disease, but as a collection of quite predictable diseases caused by the deterioration of the body." The two main arguments used are that aging is both inevitable and universal while diseases are not. However, not everyone agrees. Harry R. Moody, director of academic affairs for AARP, notes that what is normal and what is disease strongly depend on a historical context. David Gems, assistant director of the Institute of Healthy Ageing, argues that aging should be viewed as a disease. In response to the universality of aging, David Gems notes that it is as misleading as arguing that Basenji are not dogs because they do not bark. Because of the universality of aging he calls it a "special sort of disease". Robert M. Perlman, coined the terms "aging syndrome" and "disease complex" in 1954 to describe aging.

The discussion whether aging should be viewed as a disease or not has important implications. One view is, this would stimulate pharmaceutical companies to develop life extension therapies and in the United States of America, it would also increase the regulation of the anti-aging market by the Food and Drug Administration (FDA). Anti-aging now falls under the regulations for cosmetic medicine which are less tight than those for drugs.

Beliefs and methods

Senolytics and prolongevity drugs

A senolytic (from the words senescence and -lytic, "decomposition or breakdown") 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. A goal of this research is to discover or develop agents to delay, prevent, alleviate, or reverse age-related diseases. Removal of senescent cells with senolytics has been proposed as a method of enhancing immunity during aging.

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. Senomorphic effects may be one major effect mechanism of a range of prolongevity drug candidates. Such candidates are however typically not studied for just one mechanism, but multiple. There are biological databases of prolongevity drug candidates under research as well as of potential gene/protein targets. These are enhanced by longitudinal cohort studies, electronic health records, computational (drug) screening methods, computational biomarker-discovery methods and computational biodata-interpretation/personalized medicine methods.

Besides rapamycin and senolytics, the drug-repurposing candidates studied most extensively include metformin, acarbose, spermidine and NAD+ enhancers.

Many prolongevity drugs are synthetic alternatives or potential complements to existing nutraceuticals, such as various sirtuin-activating compounds under investigation like SRT2104In some cases pharmaceutical administration is combined with that of neutraceuticals – such as in the case of glycine combined with NAC. Often studies are structured based on or thematize specific prolongevity targets, listing both nutraceuticals and pharmaceuticals (together or separately) such as FOXO3-activators.

Researchers are also exploring ways to mitigate side-effects from such substances (possibly most notably rapamycin and its derivatives) such as via protocols of intermittent administration and have called for research that helps determine optimal treatment schedules (including timing) in general.

Diets and supplements

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. Other reviews have found no relationship between vitamin E and other vitamins with mortality. Vitamin D supplementation of various dosages is investigated in trials and there also is research into GlyNAC (see above).

Complications

Complications of antioxidant supplementation (especially continuous high dosages far above the RDA) include that reactive oxygen species (ROS), which are mitigated by antioxidants, "have been found to be physiologically vital for signal transduction, gene regulation, and redox regulation, among others, implying that their complete elimination would be harmful". In particular, one way of multiple they can be detrimental is by inhibiting adaptation to exercise such as muscle hypertrophy (e.g. during dedicated periods of caloric surplus). There is also research into stimulating/activating/fueling endogenous antioxidant generation, in particular e.g. of neutraceutical glycine and pharmaceutical NAC. Antioxidants can change the oxidation status of different e.g. tissues, targets or sites each with potentially different implications, especially for different concentrations. A review suggests mitochondria have a hormetic response to ROS, whereby low oxidative damage can be beneficial.

Dietary restriction

As of 2021, there is no clinical evidence that any dietary restriction practice contributes to human longevity.

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. Research is identifying the key beneficial components of the Mediterranean diet. Studies suggest dietary changes are a factor of national relative rises in life-span.

Optimal diet

Approaches to develop optimal diets for health- and lifespan (or "longevity diets") include:

Other approaches

Further advanced biosciences-based approaches include:

  • Genetic and epigenetic alterations: Human genetic enhancement for pro-longevity and protective genes – see genetics of aging
  • Cellular reprogramming: in vivo reprogramming to complement or augment human regenerative capacity and rejuvenate or replace cells
  • Epigenetic reprogramming: early-stage research about rejuvenating/repairing epigenetic machinery
  • Stem-cell interventions: "Increasing the number and quality of stem cells and activate regenerative signals"
  • Nanomedicine: early-stage research of in vivo pro-longevity nanotechnology
  • Tissue engineering: of tissues and organs (see also: xenotransplantation and artificial organ)
  • Endogenous circulating biomolecules: Blood proteins of blood from young animals have shown some pro-longevity potential in animal studies (e.g. via transfer of blood or plasma, and of plasma proteins). Moreover, exerkines – signalling biomolecules released during/after exercise – have also shown promising results. Exerkines include myokines. Extracellular vesicles were shown to be secreted concomitantly with exerkines and are also investigated. (See also: body fluid and cerebrospinal fluid)
  • Personalized interventions: future studies may tailor and investigate personalized medicine-type interventions. For instance, effects of interventions or e.g. dosages may vary per age and/or genome. A review suggests that the field of precision medicine and geroscience will have to interact closely (see also: combination therapy)
  • Peptides: such as MOTS-c released by mitochondria
  • Mitochondria modulation: early-stage research indicates mitochondrial interventions such as mitochondrial transplantation may have potential to be efficacious

Within the field

There is a need and research into the development of aging biomarkers such as the epigenetic clock "to assess the ageing process and the efficacy of interventions to bypass the need for large-scale longitudinal studies". Such biomarkers may also include in vivo brain imaging.

Reviews sometimes include structured tables that provide systematic overviews of intervention/drug candidates with a review calling for integrating "current knowledge with multi-omics, health records, and drug safety data to predict drugs that can improve health in late life" and listing major outstanding questionsBiological databases of prolongevity drug candidates under research as well as of potential gene/protein targets include GenAge, DrugAge and Geroprotectors.

A review has pointed out that the approach of "'epidemiological' comparison of how a low versus a high consumption of an isolated macronutrient and its association with health and mortality may not only fail to identify protective or detrimental nutrition patterns but may lead to misleading interpretations". It proposes a multi-pillar approach, and summarizes findings towards constructing – multi-system-considering and at least age-personalized dynamic – refined longevity diets. Epidemiological-type observational studies included in meta-analyses should according to the study at least be complemented by "(1) basic research focused on lifespan and healthspan, (2) carefully controlled clinical trials, and (3) studies of individuals and populations with record longevity".

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.

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.

Klotho and exerkines (see above) like irisin are being investigated for potential pro-longevity therapies.

Lifestyle factors

Loneliness/isolation, social life and support, exercise/physical activity (partly via neurobiological effects and increased NAD+ levels), psychological characteristics/personality (possibly highly indirectly), sleep duration, circadian rhythms (patterns of sleep, drug-administration and feeding), type of leisure activities, not smoking, altruistic emotions and behaviors, subjective well-being, mood and stress (including via heat shock protein) are investigated as potential (modulatable) factors of life extension.

Healthy lifestyle practices and healthy diet have been suggested as "first-line function-preserving strategies, with pharmacological agents, including existing and new pharmaceuticals and novel 'nutraceutical' compounds, serving as potential complementary approaches".

Societal strategies

Life expectancy vs healthcare spending of rich OECD countries. US average of $10,447 in 2018.

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 (a measure similar to years of potential life lost) is considered to be unavoidable.

Regular screening and doctor visits has been suggested as a lifestyle-societal intervention. (See also: medical test and biomarker)

Health policy and changes to standard healthcare could support the adoption of the field's conclusions – a review suggests that the longevity diet would be a "valuable complement to standard healthcare and that, taken as a preventative measure, it could aid in avoiding morbidity, sustaining health into advanced age" as a form of preventive healthcare.

It has been suggested that in terms of healthy diets, Mediterranean-style diets could be promoted by countries for ensuring healthy-by-default choices ("to ensure the healthiest choice is the easiest choice") and with highly effective measures including dietary education, food checklists and recipes that are "simple, palatable, and affordable".

A review suggests that "targeting the aging process per se may be a far more effective approach to prevent or delay aging-associated pathologies than treatments specifically targeted to particular clinical conditions".

Low ambient temperature

Low ambient temperature as a physical factor affecting free radical levels was identified as a treatment producing exceptional lifespan increase in Drosophila melanogaster and other living beings.

Young blood transfusion

As of 2017, some clinics offered injection of blood plasma from young donors. The alleged benefits of the treatment, none of which had been proven, included a longer life. The approach was based on parabiosis studies in mice.

In 2019, after receiving an FDA warning letter to cease giving people plasma infusions, one American company that promoted the treatment, Ambrosia, withdrew from clinical trials it had conducted without FDA approval. The FDA had stated "that some patients are being preyed upon by unscrupulous actors touting treatments of plasma from young donors as cures and remedies."

The treatment appeared in HBO's Silicon Valley fiction series.

Microbiome alterations

Fecal microbiota transplantation and probiotics are being investigated as means for life and healthspan extension.

Mind uploading

One hypothetical future strategy that, as some suggest, "eliminates" the complications related to a physical body, involves the copying or transferring (e.g. by progressively replacing neurons with transistors) of a conscious mind from a biological brain to a non-biological computer system or computational device. The basic idea is to scan the structure of a particular brain in detail, and then construct a software model of it that is so faithful to the original that, when run on appropriate hardware, it will behave in essentially the same way as the original brain. Whether or not an exact copy of one's mind constitutes actual life extension is matter of debate.

However, critics argue that the uploaded mind would simply be a clone and not a true continuation of a person's consciousness.

Some scientists believe that the dead may one day be "resurrected" through simulation technology.

Aging brain

From Wikipedia, the free encyclopedia

Aging brain refers to biological and functional changes that occur in the brain as individuals advance in age. It encompasses both the normal alterations which are universally experienced and abnormalities induced by illnesses, diagnosed or not. The concept is most often used in relation to humans.

Since life extension is only pertinent if accompanied by healthspan extension, and, more importantly, by preserving brain health and cognition, finding rejuvenating approaches that act simultaneously in peripheral tissues and in brain function is a key strategy in the development of rejuvenation technology.

Aging is a major risk factor for most common neurodegenerative diseases, including mild cognitive impairment, dementias including Alzheimer's disease, cerebrovascular disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. While much research has focused on diseases of aging, there are few informative studies on the molecular biology of the aging brain in the absence of neurodegenerative disease or the neuropsychological profile of healthy older adults. However, research suggests that the aging process is associated with several structural, chemical, and functional changes in the brain as well as a host of neurocognitive changes. Recent reports in model organisms suggest that as organisms age, there are distinct changes in the expression of genes at the single neuron level. This page is an overview of the changes associated with human brain aging, including aging without concomitant diseases.

Structural changes

Human brain in the sagittal plane
Ventricles of the brain

Aging entails many physical, biological, chemical, and psychological changes and the brain is no exception to this phenomenon. These various changes have attempted to be mapped by conceptual models like the Scaffolding Theory of Aging and Cognition (STAC) in 2009. The STAC model looks at factors like neural changes to the white matter, dopamine depletion, shrinkage, and cortical thinning. CT scans have found that the cerebral ventricles expand as a function of age. More recent MRI studies have reported age-related regional decreases in cerebral volume. Regional volume reduction is not uniform; some brain regions shrink at a rate of up to 1% per year, whereas others remain relatively stable until the end of the life-span. The brain is very complex, and is composed of many different areas and types of tissue, or matter. The different functions of different tissues in the brain may be more or less susceptible to age-induced changes. The brain matter can be broadly classified as either grey matter, or white matter. Grey matter consists of cell bodies in the cortex and subcortical nuclei. White matter consists of tightly packed myelinated axons connecting the neurons to each other and with the periphery.

Loss of neural circuits and brain plasticity

Brain plasticity refers to the brain's ability to change structure and function. This ties into the common phrase, "if you don't use it, you lose it," which is another way of saying, "if you do not use it, your brain will devote less somatotopic space for it". One proposed mechanism for the observed age-related plasticity deficits in animals is the result of age-induced alterations in calcium regulation. The changes in the organism's abilities to handle calcium will ultimately influence neuronal firing and the ability to propagate action potentials, which in turn would affect the ability of the brain to alter its structure or function (i.e. its plastic nature). Due to the complexity of the brain, with all of its structures and functions, it is logical to assume that some areas would be more vulnerable to aging than others. Two circuits worth mentioning here are the hippocampal and neocortical circuits. It has been suggested that age-related cognitive decline is due in part not to neuronal death but to synaptic alterations. Evidence in support of this idea from animal work has also suggested that this cognitive deficit is due to functional and biochemical factors such as changes in enzymatic activity, chemical messengers, or gene expression in cortical circuits.

Thinning of the cortex

Lobes of the human brain

Advances in MRI technology have provided the ability to see the brain structure in great detail in an easy, non-invasive manner in vivo. Bartzokis et al., has noted that there is a decrease in grey matter volume between adulthood and old age, whereas white matter volume was found to increase from age 19–40, and decline after this age. Studies using Voxel-based morphometry have identified areas such as the insula and superior parietal gyri as being especially vulnerable to age-related losses in grey matter of older adults. Sowell et al., reported that the first 6 decades of an individual's life were correlated with the most rapid decreases in grey matter density, and this occurred over dorsal, frontal, and parietal lobes on both interhemispheric and lateral brain surfaces. It is also worth noting that areas such as the cingulate gyrus, and occipital cortex surrounding the calcarine sulcus appear exempt from this decrease in grey matter density over time. Age effects on grey matter density in the posterior temporal cortex appear more predominantly in the left versus right hemisphere, and were confined to posterior language cortices. Certain language functions such as word retrieval and production were found to be located to more anterior language cortices, and deteriorate as a function of age. Sowell et al., also reported that these anterior language cortices were found to mature and decline earlier than the more posterior language cortices. It has also been found that the width of sulcus not only increases with age, but also with cognitive decline in the elderly.

Morphology and microstructure

Age-related decrease in gray matter volume was the largest contribution to changes in brain volume. Moreover, neuronal density appears to decrease, white matter microstructure gets altered and energy metabolism in the cerebellum gets altered. General cortical atrophy occurs in aging and e.g. the caudate nucleus volume appears to decrease.

There is converging evidence from cognitive neuroscientists around the world that age-induced cognitive deficits may not be due to neuronal loss or cell death, but rather may be the result of small region-specific changes to the morphology of neurons. Studies by Duan et al., have shown that dendritic arbors and dendritic spines of cortical pyramidal neurons decrease in size and/or number in specific regions and layers of human and non-human primate cortex as a result of age (Duan et al., 2003; morph). A 46% decrease in spine number and spine density has been reported in humans older than 50 compared with younger individuals. An electron microscopy study in monkeys reported a 50% loss in spines on the apical dendritic tufts of pyramidal cells in prefrontal cortex of old animals (27–32 years old) compared with young ones (6–9 years old).

Neurofibrillary tangles

Tau protein disorders cause microtubule destruction and formation of neurofibrillary tangles.

Age-related neuropathologies such as Alzheimer's disease, Parkinson's disease, diabetes, hypertension and arteriosclerosis make it difficult to distinguish the normal patterns of aging. One of the important differences between normal aging and pathological aging is the location of neurofibrillary tangles. Neurofibrillary tangles are composed of paired helical filaments (PHF). In normal, non-demented aging, the number of tangles in each affected cell body is relatively low and restricted to the olfactory nucleus, parahippocampal gyrus, amygdala and entorhinal cortex. As the non-demented individual ages, there is a general increase in the density of tangles, but no significant difference in where tangles are found.

The other main neurodegenerative contributor commonly found in the brain of patients with AD is amyloid plaques. However, unlike tangles, plaques have not been found to be a consistent feature of normal aging.

Role of oxidative stress

Cognitive impairment has been attributed to oxidative stress, inflammatory reactions and changes in the cerebral microvasculature. The exact impact of each of these mechanisms in affecting cognitive aging is unknown. Oxidative stress is the most controllable risk factor and is the best understood. The online Merriam-Webster Medical Dictionary defines oxidative stress as, "physiological stress on the body that is caused by the cumulative damage done by free radicals inadequately neutralized by antioxidants and that is held to be associated with aging." Hence oxidative stress is the damage done to the cells by free radicals that have been released from the oxidation process.

Compared to other tissues in the body, the brain is deemed unusually sensitive to oxidative damage. Increased oxidative damage has been associated with neurodegenerative diseases, mild cognitive impairment and individual differences in cognition in healthy elderly people. In 'normal aging', the brain is undergoing oxidative stress in a multitude of ways. The main contributors include protein oxidation, lipid peroxidation and oxidative modifications in nuclear and mitochondrial DNA. Oxidative stress can damage DNA replication and inhibit repair through many complex processes, including telomere shortening in DNA components. Each time a somatic cell replicates, the telomeric DNA component shortens. As telomere length is partly inheritable, there are individual differences in the age of onset of cognitive decline.

DNA damage

At least 25 studies have demonstrated that DNA damage accumulates with age in the mammalian brain. This DNA damage includes the oxidized nucleoside 8-hydroxydeoxyguanosine (8-OHdG), single- and double-strand breaks, DNA-protein cross-links and malondialdehyde adducts (reviewed in Bernstein et al.). Increasing DNA damage with age has been reported in the brains of the mouse, rat, gerbil, rabbit, dog, and human. Young 4-day-old rats have about 3,000 single-strand breaks and 156 double-strand breaks per neuron, whereas in rats older than 2 years the level of damage increases to about 7,400 single-strand breaks and 600 double-strand breaks per neuron.

Lu et al. studied the transcriptional profiles of the human frontal cortex of individuals ranging from 26 to 106 years of age. This led to the identification of a set of genes whose expression was altered after age 40. They further found that the promoter sequences of these particular genes accumulated oxidative DNA damage, including 8-OHdG, with age (see DNA damage theory of aging). They concluded that DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a pattern of brain aging that starts early in life.

Immune system and fluids

Blood–brain barrier permeability, neuroinflammation and neurodegeneration, and gut microbiota-induced systemic chronic inflammation appear to be linked and interact with aging, e.g. as gut microbiota homeostasis could be disturbed by increasing age. According to a review, neuroinflammatory changes, "including microglial activation and production of inflammatory cytokines", occur with normal aging.

Fluids

Cerebral blood flow was shown to decrease 0.3-0.5% per year in healthy ageing. An efficiently functioning glymphatic system, involved in waste clearance, may be important for maintaining brain health and its transport efficiency appears to be declining with aging. Factors in the circulation have been shown to modulate ageing and to rejuvenate the brain.

Chemical changes

A labelled line drawing of dopamine pathways superimposed on a drawing of the human brain.
Major dopamine pathways.
 
As part of the reward pathway, dopamine is manufactured in nerve cell bodies located within VTA and is released in the nucleus accumbens and the prefrontal cortex. The motor functions of dopamine are linked to a separate pathway, with cell bodies in the substantia nigra that manufacture and release dopamine into the striatum.
Dopamine and serotonin functions and pathways

In addition to the structural changes that the brain incurs with age, the aging process also entails a broad range of biochemical changes. More specifically, neurons communicate with each other via specialized chemical messengers called neurotransmitters. Several studies have identified a number of these neurotransmitters, as well as their receptors, that exhibit a marked alteration in different regions of the brain as part of the normal aging process.

Dopamine

An overwhelming number of studies have reported age-related changes in dopamine synthesis, binding sites, and number of receptors. Studies using positron emission tomography (PET) in living human subjects have shown a significant age-related decline in dopamine synthesis, notably in the striatum and extrastriatal regions (excluding the midbrain). Significant age-related decreases in dopamine receptors D1, D2, and D3 have also been highly reported. A general decrease in D1 and D2 receptors has been shown, and more specifically a decrease of D1 and D2 receptor binding in the caudate nucleus and putamen. A general decrease in D1 receptor density has also been shown to occur with age. Significant age-related declines in dopamine receptors, D2 and D3 were detected in the anterior cingulate cortex, frontal cortex, lateral temporal cortex, hippocampus, medial temporal cortex, amygdala, medial thalamus, and lateral thalamus. One study also indicated a significant inverse correlation between dopamine binding in the occipital cortex and age. Postmortem studies also show that the number of D1 and D2 receptors decline with age in both the caudate nucleus and the putamen, although the ratio of these receptors did not show age-related changes. The loss of dopamine with age is thought to be responsible for many neurological symptoms that increase in frequency with age, such as decreased arm swing and increased rigidity. Changes in dopamine levels may also cause age-related changes in cognitive flexibility.

Serotonin

Decreasing levels of different serotonin receptors and the serotonin transporter (5-HTT), have also been shown to occur with age. Studies conducted using PET methods on humans, in vivo, show that levels of the 5-HT2 receptor in the caudate nucleus, putamen, and frontal cerebral cortex, decline with age. A decreased binding capacity of the 5-HT2 receptor in the frontal cortex was also found, as well as a decreased binding capacity of the serotonin transporter (5-HHT) in the thalamus and the midbrain. Postmortem studies on humans have indicated decreased binding capacities of serotonin and a decrease in the number of S1 receptors in the frontal cortex and hippocampus as well as a decrease in affinity in the putamen.

Glutamate

Expression of glutamate transporter 1 in glial cell facilitates reuptake of glutamate and decreases extracellular glutamate concentration

Glutamate is another neurotransmitter that tends to decrease with age. Studies have shown older subjects to have lower glutamate concentration in the motor cortex compared to younger subjects. A significant age-related decline especially in the parietal gray matter, basal ganglia, and to a lesser degree, the frontal white matter, has also been noted. Although these levels were studied in the normal human brain, the parietal and basal ganglia regions are often affected in degenerative brain diseases associated with aging and it has therefore been suggested that brain glutamate may be useful as a marker of brain diseases that are affected by aging.

Neuropsychological changes

Changes in orientation

Orientation is defined as the awareness of self in relation to one's surroundings. Often orientation is examined by distinguishing whether a person has a sense of time, place, and person. Deficits in orientation are one of the most common symptoms of brain disease, hence tests of orientation are included in almost all medical and neuropsychological evaluations. While research has primarily focused on levels of orientation among clinical populations, a small number of studies have examined whether there is a normal decline in orientation among healthy aging adults. Results have been somewhat inconclusive. Some studies suggest that orientation does not decline over the lifespan. For example, in one study 92% of normal elderly adults (65–84 years) presented with perfect or near perfect orientation. However some data suggest that mild changes in orientation may be a normal part of aging. For example, Sweet and colleagues concluded that "older persons with normal, healthy memory may have mild orientation difficulties. In contrast, younger people with normal memory have virtually no orientation problems." So although current research suggests that normal aging is not usually associated with significant declines in orientation, mild difficulties may be a part of normal aging and not necessarily a sign of a particular pathology.

Changes in attention

Many older adults notice a decline in their attentional abilities. Attention is a broad construct that refers to "the cognitive ability that allows us to deal with the inherent processing limitations of the human brain by selecting information for further processing". Since the human brain has limited resources, people use their attention to zone in on specific stimuli and block out others.

If older adults have fewer attentional resources than younger adults, we would expect that when two tasks must be carried out at the same time, older adults' performance will decline more than that of younger adults. However, a large review of studies on cognition and aging suggest that this hypothesis has not been wholly supported. While some studies have found that older adults have a more difficult time encoding and retrieving information when their attention is divided, other studies have not found meaningful differences from younger adults. Similarly, one might expect older adults to do poorly on tasks of sustained attention, which measure the ability to attend to and respond to stimuli for an extended period of time. However, studies suggest that sustained attention shows no decline with age. Results suggest that sustained attention increases in early adulthood and then remains relatively stable, at least to the middle of the eighth decade of life. More research is needed on how normal aging impacts attention after age eighty.

It is worth noting that there are factors other than true attentional abilities that might relate to difficulty paying attention. For example, it is possible that sensory deficits impact older adults' attentional abilities. In other words, impaired hearing or vision may make it more difficult for older adults to do well on tasks of visual and verbal attention.

Changes in memory

Many different types of memory have been identified in humans, such as declarative memory (including episodic memory and semantic memory), working memory, spatial memory, and procedural memory. Studies done, have found that memory functions, more specifically those associated with the medial temporal lobe are especially vulnerable to age-related decline. A number of studies utilizing a variety of methods such as histological, structural imaging, functional imaging, and receptor binding have supplied converging evidence that the frontal lobes and frontal-striatal dopaminergic pathways are especially affected by age-related processes resulting in memory changes.

Changes in language

Changes in performance on verbal tasks, as well as the location, extent, and signal intensity of BOLD signal changes measured with functional MRI, vary in predictable patterns with age. For example, behavioral changes associated with age include compromised performance on tasks related to word retrieval, comprehension of sentences with high syntactic and/or working memory demands, and production of such sentences.

Brain activation patterns

The left inferior frontal junction and left anterior cuneus/precuneus were the only regions in a larger set of regions associated with executive functions, that consistently showed age differences in brain activity.

Changes in learning and behavioral flexibility

Learning is often more efficient in children and takes longer or is more difficult with age. A study using neuroimaging identified rapid neurotransmitter GABA boosting as a major potential explanation-component for why that is.

Behavioral flexibility can refer to efficiently and appropriately adapting to different situations and changing environmental demands, including the speed of adaptation, and to the capacity to develop solutions to novel problems or novel solutions to old problems. Studies indicate late-stage aging, and/or late-life dementias, decreases behavioral flexibility and impair deliberation about courses of action.

Genetic changes

Variation in the effects of aging among individuals can be attributed to both genetic, health, and environmental factors. As in so many other science disciplines, the nature versus nurture debate is an ongoing conflict in the field of cognitive neuroscience. The search for genetic factors has always been an important aspect in trying to understand neuropathological processes. Research focused on discovering the genetic component in developing Autosomal Dominant (AD) has also contributed greatly to the understanding the genetics behind normal or "non-pathological" aging.

Autosomal Dominant (AD) - Autosomal dominant is a pattern of inheritance characteristic of some genetic disorders. "Autosomal" means that the gene in question is located on one of the numbered, or non-sex, chromosomes. "Dominant" means that a single copy of the mutated gene (from one parent) is enough to cause the disorder.

The human brain shows a decline in function and a change in gene expression. This modulation in gene expression may be due to oxidative DNA damage at promoter regions in the genome. Genes that are down-regulated over the age of 40 include:

Genes that are upregulated include:

Measurement

Epigenetic age analysis of brain regions

The cerebellum is the youngest brain region (and probably body part) in centenarians according to an epigenetic biomarker of tissue age known as epigenetic clock: it is about 15 years younger than expected in a centenarian. By contrast, all brain regions and brain cells appear to have roughly the same epigenetic age in subjects who are younger than 80. These findings suggest that the cerebellum is better protected from aging effects, which in turn could explain why the cerebellum exhibits fewer neuropathological hallmarks of age related dementias compared to other brain regions.

Other

There is research and development of biomarkers of aging, detection systems and software systems to measure biological age of the brain. For example, a deep learning software using anatomic magnetic resonance images estimated brain age with relatively high accuracy, including detecting early signs of Alzheimer's disease and varying neuroanatomical patterns of neurological aging.

Delaying the effects of aging

The current state of biomedical technology does not allow to stop and reverse aging. However, one may potentially delay the effects and severity of its symptoms. While there is no consensus of efficacy, the following are reported as delaying cognitive decline:

Cognitive reserve

The ability of an individual to demonstrate attenuated cognitive signs of aging despite an aging brain is called cognitive reserve. This hypothesis suggests that two patients might have the same brain pathology, with one person experiencing noticeable clinical symptoms, while the other continues to function relatively normally. Studies of cognitive reserve explore the specific biological, genetic and environmental differences which make some people more resistant to cognitive decline than others.

Intellectual quotients derived from psychometric testing have been identified as valuable proxy measures of cognitive reserve, with higher scores relative to the mean being associated with slower rates of cognitive decline. However, the rate of decline in some cognitive subdomains, such as processing speed, may be less affected by premorbid IQ. The degree of association between IQ and cognitive reserve may vary between different types of dementia.

Research

"Super Agers"

Longitudinal research studies have recently conducted genetic analyses of centenarians and their offspring to identify protective factors against the negative effects of aging. In particular, the CETP gene is linked to prevention of cognitive decline and Alzheimer's disease. Specifically, valine CETP homozygotes but not heterozygotes experienced a relative 51% less decline in memory compared to a reference group after adjusting for demographic factors and APOE status.

Nun Study

A study funded by the National Institute on Aging (NIA) began in 1986 and followed a group of 678 Roman Catholic sisters and recorded the effects of aging. The researchers used autobiographical essays collected as the nuns joined their Sisterhood. Findings suggest that early idea density, defined by number of ideas expressed and use of complex prepositions in these essays, was a significant predictor of lower risk for developing Alzheimer's disease in old age. Lower idea density was found to be significantly associated with lower brain weight, higher cerebral atrophy, and more neurofibrillary tangles.

In 1994, Religious Orders Study has begun. Its initial funding was also provided by NIA.

Inflammation

A study found that myeloid cells are drivers of a maladaptive inflammation element of brain-ageing in mice and that this can be reversed or prevented via inhibition of their EP2 signalling.

Cerebrospinal fluid

The cerebrospinal fluid circulates in the subarachnoid space around the brain and spinal cord, and in the ventricles of the brain

A study showed that infusing the nourishing cerebrospinal fluid from around brain cells of young mice into aged brains rejuvenates aspects of the brain, proving that it play a role in brain aging and inter alia identifying a protein FGF17 as a key target for potential therapeutics, including for anti-aging.

The subarachnoidal lymphatic-like membrane, whose discovery was reported around 2023, likely plays a role in cerebrospinal fluid functions and, as both a protective barrier and a host of immune cells that monitor the brain for infection and inflammation, appears to be substantially involved in major brain diseases and brain aging. It is "the host for a large population of myeloid cells [(see above)], the number of which increases in response to inflammation and aging".

Aging disparities

For certain demographics, the effects of normal cognitive aging are especially pronounced. Differences in cognitive aging might be tied to the lack of or reduced access to medical care and, as a result, suffer disproportionately from negative health outcomes. As the global population grows, diversifies, and grays, there is an increasing need to understand these inequities.

Race

African Americans

Life expectancy in the US by race
Life expectancy in the US by race and sex, with calculated sex gap
Probability of dying at various ages in the US in 2019 by race and sex.
See also male-only and female-only versions of the chart.

In the United States, Black and African American demographics disproportionately experience metabolic dysfunction with age. This has many downstream effects, but the most prominent of these is the toll on cardiovascular health. Metabolite profiles of the healthy aging index - a score that assesses neurocognitive function, among other correlates of health through the years - are associated with cardiovascular disease. Healthy cardiovascular function is critical for maintaining neurocognitive efficiency into old age. Attention, verbal learning, and cognitive set ability are related to diastolic blood pressure, triglyceride levels, and HDL cholesterol levels, respectively.

Latinos

In the US, the Latino demographic is most likely to develop metabolic syndrome - the combination of high blood pressure, high blood sugar, elevated triglyceride levels, and abdominal obesity - which not only increases the risk of cardiac events and type 2 diabetes but also is associated with lower neurocognitive function during midlife. This takes place even though life expectancy for Latinos in the US is higher than for white and black.

Among different Latin heritages, frequency of the dementia-predisposing ε4 allele of apoE4 gene was highest for Caribbean Latinos (Cubans, Dominicans, Puerto Ricans, 12.6–17.5 %) and lowest among mainland Latinos (Mexicans, Central Americans, and South Americans, 11.0–11.2 %). At the same time, frequency of the neuroprotective ε2 allele was also highest for Caribbean Latinos (5.2–8.6 %) and lowest for those of mainland heritage (2.9–3.9 %). Among mainland Latinos, the most prevalent is the "median" ε3 allele: 85.2–86.2 % compared to 73.9–81.5% among Caribbean Latinos.

Indigenous peoples

Indigenous populations are often understudied in research. Reviews of current literature studying natives in Australia, Brazil, Canada, and the United States from participants aged 45 to 94 years old reveal varied prevalence rates for cognitive impairment not related to dementia, from 4.4% to 17.7%. These results can be interpreted in the context of culturally biased neurocognitive tests, preexisting health conditions, poor access to healthcare, lower educational attainment, and/or old age.

Sex

Compared to their male counterparts, women's scores on the mini–mental state examination (MMSE) tend to decline at slightly faster rates with age. Males with mild cognitive impairment tend to show more microstructural damage than females with MCI, but seem to have a greater cognitive reserve due to larger absolute brain size and neuronal density. As a result, women tend to manifest symptoms of cognitive decline at lower thresholds than men do. This effect seems to be moderated by educational attainment - higher education is associated with later diagnosis of mild cognitive impairment as neuropathological load increases. Currently there are no known studies to identify a characteristic pattern of cognitive decline with age in transgender people.

Socioeconomic factors

Socioeconomic status is the interaction between social and economic factors. It has been demonstrated that socio-demographic factors can be used to predict cognitive profiles within older individuals to some extent.  This may be because families of higher socioeconomic status (SES) are equipped to provide their children with resources early on to facilitate cognitive development. For children in families of low SES, relatively small changes in parental income were associated with large changes in brain surface area; these losses were seen in areas associated with language, reading, executive functions, and spatial skills. Meanwhile, for children in families of high SES, small changes in parental income were associated with small changes in surface area within these regions. With respect to global cortical thickness, low SES children showed a curvilinear decrease in thickness with age while those of high SES demonstrated a steeper linear decline, suggesting that synaptic pruning is more efficient in the latter group. This trend was especially evident in the left fusiform and left superior temporal gyri - critical language and literacy supporting areas.

A study showed that 50+ aged users of the dietary program SNAP "had about 2 fewer years of cognitive aging over a 10-year period compared with non-users" despite it having nearly no conditions for the sustainability and healthiness of the food products purchased with the coupons (or coupon-credits).

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