Lifespan 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.

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) 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. The use of such hormone products, however, has not been proven to be effective or safe.

Average and maximum 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.Halliwell B, Gutteridge JMC (2007). Free Radicals in Biology and Medicine. Oxford University Press, USA, ,

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 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. 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.

Strategies

Senolytics and prolongevity drugs

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.

Such strategies as well as testing with model organisms and xenografts may attempt to or help address difficulties of trials with humans which have relatively long lifespans (compared to other animals) as well as the (larger) need to protect human health from early-trial-stage interventions (in clinical trials).

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 SRT2104. In some cases pharmaceutical administration is combined with that of neutraceuticals – such as in the case of glycine combined with NAC. Often studies are strucutured 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 .

=Complications

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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

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

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 the benefits of healthy body weight.

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). Intermittent fasting refers to periods with intervals during which no food but only water and tea/coffee (the latter reduces appetite or facilitates caloric restriction and also activates autophagy) 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 for synergistic effects with overall caloric restriction and variants of the Mediterranean diet which usually has benefits of long-term cardiovascular health and longevity.

CALERIE is a trial of prolonged continuous calorie restriction on healthy humans.

=Targeted restrictions

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Specific amino acids in the protein consumption are associated with the regulation of lifespan/ageing and their targeted restriction has been proposed for further research.

=Mechanisms

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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 (see also: mTOR inhibitors), mTOR, insulin-related pathways, sirtuins, NAD+, NFkB, and FOXO and, partly by extension, processes such as DNA repair and autophagy.

=Complications

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During periods of caloric restriction, higher protein intakes "may be required to maximize muscle retention in lean, resistance-trained subjects" and "resistance training (RT) can attenuate muscle loss during caloric restriction" 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". Reviews have clarified that the permanent or periodic caloric restriction is conducted in such a way that no malnutrition occurs .

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. It shares various characteristics with the similarly beneficial Okinawa diet. Potential anti-aging mechanisms of various nutrients are not yet understood. Shares of macronutrients and level of caloric intake may also be of significance, including in periods when no dietary restriction occurs – such as not having a fat-intake that is too low and not having a prolonged caloric surplus or caloric deficit that is too large.

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

= Microbiome

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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 (multi-strain) probiotics and synbiotics, and fecal microbiota transplantation are being investigated for life extension, mainly for prolonging healthspan, with many important questions being unresolved.

=Optimal diet

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Approaches to develop optimal diets for health- and lifespan (or "longevity diets") include:
* modifying or further particularizing the Mediterranean diet as the baseline via nutrition science. For instance, via:
**(additional) increase in plant-based (but protein-rich) foods alongside additional restriction of meat intake – meat reduction is (or can be) typically healthy,
**regular moderate consumption of green tea or (filtered) coffee while ensuring adequate calcium intake
**(additional) increase in omega-3-containing seafoods (see also: algal oil)
**adding various foods thought to be healthy (e.g. due to results about various mechanistic effects) to the regular dietary consumption patterns (see also: functional food)
***increasing the intake of high-spermidine foods – studies suggest spermidine could extend lifespan, with high amounts that are larger than common supplements being present in fungi (e.g. mushrooms) and green peas
***increasing resistant starch-intake – legumes, especially e.g. green peas contain large amounts of resistant starch, especially if pre-cooked as cooling the cooked peas in a refrigerator substantially increases the resistant starch content due to starch retrogradation. It is a prebiotic (see Microbiome) and may promote healthy aging.
**keeping alcohol consumption of any type at a minimum – conventional Mediterranean diets include alcohol consumption (i.e. of wine), which is under research due to data suggesting negative long-term brain impacts even at low/moderate consumption levels. Anthocyanins which are present in red wine and suggested along with other flavanols to be a candidate for further longevity research are also present in comparable concentrations in bilberry and elderberry
**fully replacing refined grains – some guidelines of Mediterranean diets do not clarify or include the principle of whole-grain consumption instead of refined grains. Whole-grain are a significant source of spermidine and are associated with longevity. They are main characteristic pillar of Mediterranean diets according to multiple reviews.
**aiming for a sufficient level of food variety and diversity – which some guidelines of Mediterranean diets do not clarify or include. One review suggests that food variety and diversity could be a factor of diet quality, and another review indicates that sufficient food variety may at least in some specific cases "increase intake of important nutrients and positively affect the gut microbiome structure and function". The required level of food variety may or may not be low and vary per person and diet.
**completely eliminating processed foods from the diet – some guidelines of Mediterranean diets may not clarify this principle. Diets associated with longevity are characterized by minimally processed foods.
**adjusting the diet for personal characteristics such as age as effects of e.g. macronutrient intake can vary per age
* 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 (shifting diets towards) 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". Lay summary:

Nutraceuticals

Beyond, research into senolytics and (synthetic) prolongevity-drugs, vitamins and antioxidants, prebiotics and probiotics, there are neutraceuticals – dietary supplements and bioactive plant compounds (phytochemicals) but not pharmaceuticals – that are being investigated in life sciences, nutrition science and gerontology for potential health- and lifespan extension in healthy humans. Sometimes, their use is researched or recommended as a way to correct nutritional deficiencies from switching to otherwise healthy foods – in particular from replacing meat consumption with a higher intake of plant-based foods. Especially, but not only, in such cases the supplementation of minerals and various specific micronutrients is investigated. Correcting magnesium deficiency for instance could prolong life. Many supplements are researched primarily for potential improvements in health and healthspan rather than for extending lifespan.

Some studies hypothesize that relative health and longevity benefits of various foods and diets can be largely or to a large part attributed to the nutraceuticals they contain. Some studies suggest increasing the intake of specific foods based on such results, while some investigate supplementation, including of dosages that are impractical to achieve with whole foods.

Researched substances include various polyphenols such as pterostilbene or flavonoids, notably epicatechin. Some herbal-extracts like rhodiola rosea are also being investigated due to results of tests with model organisms. Some of these are AMPK activator

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