Aging interventions: A look at current approaches
Both public and scholarly interest in aging research has been growing rapidly over recent years. This has triggered a proliferation of anti-aging technologies and aging interventions, ranging from simple lifestyle changes aimed at slowing aging all the way to radical regenerative technologies that may someday turn back our biological clocks. Taking in this ever-expanding array of interventions can be disorienting; it is easy to get lost in the unceasing stream of new research, new trials, and new products hitting the market. Meanwhile, it is essential — but not always easy — for the consumer to differentiate legitimate interventions backed by reputable peer-reviewed research from questionable therapies peddled by malfeasant or overly impatient entrepreneurs.
That is why we have leveraged our expertise to assemble a list of existing aging interventions that are backed by legitimate research, and which show a real possibility of contributing to the eventual development of an approach to slow or even reverse aging. Here we describe and rank existing interventions based on their potential to have an impact on aging. Though we have included a full range of interventions in our summary, at Centaura we are convinced that an effective treatment for aging will have to rely on the more radical anti-aging technologies, such as regenerative medicine.
Category: Dietary and/or drug
Calorie restriction (generally defined as a 20–50% reduction in daily caloric intake) has been shown to lengthen lifespan across animal species. For certain species, this effect can be quite significant: in mice and small, short-lived primates, proper calorie restriction can lead to an increase in lifespan exceeding 40%. However, these gains in longevity promise to be less drastic in humans, as the life-lengthening effects of caloric restriction are inversely related to species lifespan.
Despite its limited life-extending potential, calorie restriction has also been shown to reduce the incidence of cardiovascular diseases, diabetes, and cancer in individuals, leading to an increased healthspan and improved quality of life in old age.
Calorie restriction can be achieved via dietary measures, or via pharmaceuticals that mimic calorie restriction on the cellular level. These drugs, called calorie restriction mimetics, include resveratrol, rapamycin, and metformin, among other compounds.
Ultimately, although calorie restriction promises some increase in lifespan and offers the undeniable benefits of being non-invasive, economical, and simple to implement, it is not an effective solution to aging. Due to the relatively long lifespan of humans, even a full lifetime of dedicated calorie restriction could promise no more than 5–10 years of added longevity.
Boosting NAD+ level
Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme found in every cell of the human body. It is involved in a myriad of critical processes ranging from DNA repair to production of cellular energy and regulation of sleep/wake cycles.
Starting at about 40 years old, levels of NAD+ (the oxidized form of NAD) in the human body begin to sharply decline. By 60 years of age, over 50% of NAD+ can be depleted from tissues. The depletion of NAD+ has been associated with hallmarks of aging and with a host of age-related pathologies, including Alzheimer’s disease, heart disease, and metabolic disorders.
Consequently, it comes as little surprise that supplements boosting NAD+ levels in the body have been considered as a potential treatment for aging. Animal trials have shown boosting NAD+ levels to increase lifespan in yeasts, worms, and mice, and data suggests that mitochondrial function in old mice can be partially rejuvenated by increasing levels of the coenzyme.
With these initial positive results, a number of companies have already begun marketing dietary supplements such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), which have been shown to boost NAD+ levels in humans. However, the safety and effectiveness of these supplements is still not well understood. A body of research is growing that links NAD+ with cancer metabolisms, suggesting that NAD+ and associated enzymes may fuel cancer growth.
Thus, despite positive initial results in animal trials, boosting NAD+ levels has not been shown to be a safe or effective aging treatment. More studies are needed to assess the oncological ramifications of supplements such as NR and NMN, and the effects of boosted NAD+ on aging are still unclear at best.
As we age, an increasing proportion of our bodies’ cells become senescent. Senescent cells are sometimes described as “zombie cells”: though they remain metabolically active, they lose their ability to reproduce and stop contributing to normal organ function. Strikingly, then even become metabolically hyperactive, releasing harmful chemicals as ROS (reactive oxygen species) and pro-inflammatory cytokines, which drive deleterious aging-related processes and lead to the creation of yet greater numbers of senescent cells. In extreme cases, in organisms with advanced age as many as 15% of cells composing individual organ systems were found to be senescent.
Senolytic drugs are an emerging class of pharmaceuticals that aim to kill senescent cells and clear them out of an organism undergoing senolytic therapy. The hope is that by reducing the proportion of senescent cells in an organism, age-related pathologies such as chronic inflammation and cancer can be prophylactically treated. Though still largely untested in humans, in animal trials senolytic drugs have been shown to successfully reduce the SASP (senescence-associated secretory phenotype) and increase the lifespan of mice by up to 20%.
Despite the promise senolytics offer in treating one of the hallmarks of aging, studies also warn of undesirable consequences that may result from their use. Senescent cells have been shown to play a role in cellular reprogramming and wound healing, and reducing their numbers too drastically could lead to a separate host of pathologies. Ultimately, the long-term effects of senolytics are still not well understood. Furthermore, as with other insufficiently radical therapies, senolytic drugs do not promise extreme increases in healthy lifespan and would likely add years to life rather than decades or centuries.
Cleaving extracellular crosslinks and removing aggregates
Though the primary hallmarks of aging are characterized by intracellular processes, some aging-related processes have also been shown to occur in the extracellular matrix (ECM) — the exterior space around and between cells.
One such process is the accumulation of advanced glycation end-products, or AGEs — waste products that bind to essential proteins such as collagen, clogging up the ECM, inhibiting intercellular interactions and cellular migration within tissues, and creating a less favorable extracellular environment. These AGE crosslinks are thought to contribute to pathologies such as hypertension, diabetes, and the degradation of skin quality with age. Researchers have been working to develop designer enzymes that can cut through these crosslinks, restoring tissue quality and elasticity. They have also developed glucosepane-binding antibodies (glucosepane is the most abundant AGE in the ECM and thought to be the greatest contributor to AGE-related pathologies), which promise to help break up glucosepane crosslinks. Despite initial positive results in animal trials, the development of these treatments is still in its relatively early stages, and it is unknown how effective they will ultimately prove in human subjects.
Amyloids, problematic fibrillar protein aggregates, are another extracellular waste product associated with aging-related pathologies. Notably, buildups of amyloid beta around brain cells have been shown to play a critical role in Alzheimer’s disease, and many hundreds of millions of dollars in investment have been poured into research that aims to find techniques which clear out these deposits. However, after more than a decade of dedicated investment into amyloid beta therapies, there is little to be seen in the way of concrete progress. In recent years, investors have begun to see this treatment as largely fruitless and have shifted their focus towards senolytics, which have been shown to have a greater effect in treating late-stage Alzheimer’s patients.
These techniques, though undoubtedly an important vector in anti-aging research, have so far proven mostly fruitless despite massive, long-term investment. Whether they could ever prove an effective treatment for humans remains unknown.
It is unlikely that “mild” aging interventions such as dietary measures, geroprotectors, and senolytics will ever succeed in permanently staving off aging processes in cells and tissues. Hence, tissues will age and it will become necessary to implement regenerative interventions to “turn back” their biological clocks.
Category: Radical technology
The thymus gland is an organ of the immune system located in the chest, above the heart. One of the thymus’s essential functions is that it produces thymus cell lymphocytes, or T cells, which kill infected cells, activate other immune cells, produce cytokines, and regulate the immune response. Beginning in early adulthood, the size of the thymus decreases and T cell production is reduced. This makes the body more susceptible to inflammation and to diseases that are associated with age.
Therapies to improve and restore thymus function have emerged as a promising strategy to reverse aging of the immune system. In 2014, the thymus became the first organ to be successfully regenerated and restored to a more vital, younger state in a living organism. In humans, the direct effect of thymus recovery has yet to be fully investigated.
Category: Radical technology
Telomeres are segments of repeated genetic information found at the ends of each of our chromosomes. They act as protective “caps” in our genome — a margin of discardable nucleotides that protect our really important genes. As we age, our telomeres gradually wear away, increasing the likelihood of genetic damage and thereby increasing genomic instability, which is one of the hallmarks of aging. This gradual wear, referred to as telomere attrition, occurs with each cycle of cell division.
Although the rate of telomere attrition can be influenced by lifestyle factors such as diet and physical activity, the magnitude of this effect is not great, and shortened telomeres are an inevitability for all humans as they age. By contrast, in certain animal models telomere elongation has been observed. Notably, in starfish that have suffered injuries and regenerated limbs, telomeres have been shown to lengthen relative to their pre-injury state. If a technique can be developed to reliably lengthen telomeres in humans, it is believed that age-related processes such as cellular senescence, apoptosis, and the oncogenic transformation of somatic cells might be staved off, extending healthy lifespan.
Telomere extension offers great promise as a radical anti-aging therapy of the future; however, attempts that have already been made by scientists to lengthen telomeres in animal models have been shown to entail significant risks, namely a high incidence of cancer. Hopefully, with continued research and further refinement of telomere elongation techniques, this therapy can become a safe and accessible, eliminating one of the hallmarks of aging.
Category: Radical technology
Animal studies have proven that lifespan can be regulated through genetic manipulation. Furthermore, even small-scale genetic therapies can have far-reaching results — in certain test species, manipulation of even single genes has been shown to increase longevity.
In one notable study, Dr. Julius Halaschek-Wiener demonstrated that a mutation in the DAF-2 gene could double the healthy lifespan of nematode worms. In another study conducted in 2006 by scientists from the University of Michigan, it was shown that dwarf mice with a mutation in genes regulating hormone production lived about 40% longer than their counterparts lacking the mutation.
To apply similar techniques to humans, it is likely that there will be a significant number of gene segments requiring adjustment, and that these genes will be distributed in complex and varying ways both among individuals and among tissues within one individual. To meet the technical requirements of implementing such a complex gene therapy, a novel approach to massive gene editing is essential.
To understand the molecular alterations that need to be targeted, Centaura is developing a computational approach to characterize the aging processes within seaparate individuals. This approach will provide personalized Aging Profiles that will reveal the particular ways in which each individual’s tissues and organ systems are aging. With this information, targeted gene therapies such as the Human Artificial Chromosome (HAC) — a packet of supplemental genetic information inserted into a cell to alter its genetic profile — can be implemented in a way tailored to the demands of each individual system and organism, making genetic manipulation one of the most promising anti-aging technologies.
Category: Radical technology
Regenerative medicine refers to a group of medical techniques aimed at returning cells, tissues, and organs to a more youthful, less damaged state. This daunting feat will require radical interventions such as tissue engineering and the use of stem cells. Various approaches aim either to replace damaged tissues entirely or to trigger the body’s built-in repair mechanisms to “turn back the clock” on biological systems. It is likely that in order to fully regenerate all the major systems of an organism, a combination of the two approaches would be required. Though this technology holds massive potential and is already attracting the attention of a large number of researchers, it is still in its preliminary stages and has a long way to go before becoming a reality for humans.
In recent years aging research has been gaining velocity. Novel aging interventions and strategies for rejuvenating tissues and organ systems are being proposed at ever faster rates. Among these techniques and strategies, the more radical interventions promise to have the greatest hand in successfully reversing aging. This successful approach, once developed, will likely rely on a combination of several interventions, such as thymus rejuvenation, telomere elongation, and genetic editing, as each of these therapies addresses a different aspect of the aging process. Whatever the outcome of these technologies in coming years, one thing is undeniable: the current moment is a fascinating time to be involved in aging research, and aging interventions are showing more promise than ever before in finally slowing and reversing aging in humans.