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Introduction to Anti-Aging Research

Longevity and eternal youth are concepts that seem to have fascinated humans since the dawn of civilization. The Sumerian Epic of Gilgamesh, one of the oldest known written works of literature, tells the story of a king and his failed quest for immortality. Several millennia later, the ancient Greek historian Herodotus described a tribe called the Macrobians (“Long-Lived Ones”) who were all extraordinarily long-lived, supposedly due to a fountain with special water. Similar stories are attached to Alexander the Great, Sir John Mandeville, Juan Ponce de León, and other explorers said to have sought the Fountain of Youth. 

The Fountain of Youth by Lucas Cranach

Even today, we can find similar stories in every single culture around the globe. These stories usually revolve around elixirs given by the gods, daring journeys to the end of the world, or heroic deeds of suffering. Often, they are cautionary tales involving a plot twist where a long life is granted without the gift of eternal youth, so that the gift of longevity becomes a curse. In any case, the notion that our lives have a natural expiry date has inspired not only art, but also – and increasingly during the past decades – an interest in researching the causes of aging. 

Since the eve of the Industrial Revolution, we have slowly been chipping away at all the things that might kill us. The tools of science and modern medicine, including the green revolution in agriculture, vaccines, antibiotics, hospitals, and sanitation, are extending our life expectancy to the point where reaching old age is no longer a lottery. With healthier diets and lower-risk lifestyles overall, more and more humans are living out their full lifespans. This has only served to stimulate increased research into the aging process and its causes. 

Although we experience aging as a completely natural process, from an evolutionary point of view, one might expect natural selection to eliminate senescence or aging of cells, which is associated with declining reproductive potential and mortality. The fact that senescence nevertheless occurs is apparently due to the relatively weaker effects of natural selection at the later stages of life, and to the costs associated with acquisition of greater longevity.[213]

Throughout their evolutionary development, organisms are constantly engaged in trade-offs, and in an effort to achieve the ideal life history may have sacrificed survival and fertility later in life for early reproduction and survival.[214] The evolutionary genetic approach to ageing is crucial for understanding why aging evolved and how species-specific lifespan and aging are regulated.[215] After all, as mentioned above, humans were until very recently at great risk statistically of dying long before the end of their “natural” lifespan from external factors such as disease, accidents, or conflicts. Thus, in terms of species survival, the loss of “natural” lifespan may have been an acceptable trade-off.

Some hypotheses that aim to explain aging at the evolutionary and genetic levels point to the potential role of deleterious mutations that may prevent an organism from reaching its full longevity potential over life history.[216] Alternately, the “antagonistic pleiotropy” theory suggests that genes that have beneficial effects on fitness early in life, but are disadvantageous for fitness late in life would be selected because of the diminishing power of natural selection with age.[217] However, a unified model that can explain and account for all aspects of aging has yet to be found.

III

How we age: Causes and Mechanisms

What happens when we age? Scientists are only now beginning to understand the deeper underlying mechanisms at cell level that make us frail and eventually lead to death. In the following, we will look at a number of causes that contribute to human aging and discuss potential interventions that could delay, stop, or even reverse their effects. We experience the phenomenon of aging on a daily basis in our own lives, and we observe it in others – though its effects may seem more evident in some individuals than others, even though they may be the same age. Nevertheless, our knowledge about the causes of senescence, or age-related deterioration, remains incomplete, recent advances in biomedical research notwithstanding. 

Although we have not yet discovered an effective way of extending longevity, there is no doubt that such a discovery would have profound effects on human civilization. Even a modest universal extension of lifespans would entail far-reaching demographic consequences in terms of employment and work, pensions, insurance, healthcare, and many other aspects of modern society. Such changes could also be seen down to the individual level: Would we see behavioral changes if all of us could expect to live to see the long-term outcomes of our actions and life choices? 

While these questions and similar ones will have to be left unanswered for now, the following report will provide an overview of the various strands of research that are underway and the companies involved in this emerging industry. It is structured according to the nine hallmarks of aging currently known to science. Each of these factors offers a distinct research and development path for tackling the process of aging and its effects on the human body. 

For now, most of the mechanisms behind the aging process are still little understood. Scientists all over the world are doing important research to improve our knowledge in this area. This will allow us to develop medical treatments and therapies that do not target a specific disease, but aging itself. Think of it as slowing down the clock. A life extension treatment will not only help you live longer, you will also stay healthy. It is therefore reasonable to discuss the concept of “anti-aging technology” from a more holistic perspective that includes the overall quality of life. Imagine being 70 years old chronologically, but only being 50 biologically. You will maintain a more youthful body: less wrinkles, better athletic ability and so on. There are already exciting developments to take us the first step and many more to come. The first goal is to become as difficult to break as possible. Then eventually, we might be able to stop aging entirely and even reverse it. This report will show you how far we have made it, which developments to keep an eye on and what to expect for the future.  

IV

Origins of Anti-Aging Research

One of the first scientists to seriously study aging was the pioneering immunologist Elie Metchnikoff, who coined the term “gerontology” for the study of aging.[1] Metchnikoff won the 1908 Nobel Prize in Medicine for his work on the functioning of the immune system, which he also applied to his research on aging. He theorized that toxic bacteria in the gut contributed to aging and drank sour milk every day to combat them. Today, we know that the matter is far more complicated than that, but gut bacteria, our gut microbiome, do play a role.[2]

Not long after Metchnikoff’s Nobel Prize, US biochemist Clive McCay was studying nutrition. McCay fed rats on different diets to investigate how they affected their growth and development. By chance, he discovered that his rats would live longer if he fed them less.[3] 

This counterintuitive finding, dubbed “calorie restriction”, became the first proven anti-aging intervention in mammals. It also proved efficient in other rodents as well as yeast, worms and flies.[4] McCay had discovered the interconnectedness of energy, development, and aging. 

At this point, it was still believed that while the organism as a whole might age, cells were immortal. In 1961, this view was challenged when US anatomist Leonard Hayflick[5] discovered that human cells in culture are not immortal. They will only divide between 40 and 60 times and then stop. After this, they enter a phase of senescence. This phenomenon is now known as the Hayflick Limit. 

The Hayflick Limit
Source: Supertrends

Initially, it was not clear why cells would not be able to divide indefinitely. In the 1970s, Russian biologist Alexei Olovnikov found a clue. He recognized that cells could not completely replicate the ends of their chromosomes.[6]

With each division, the chromosomal ends lost a little DNA, growing slowly shorter over time. Finally, Australian biologist Elizabeth Blackburn got to the bottom of the matter. With her colleagues Carol Greider and Jack Szostak, she discovered and described the nature of structures called telomeres – a discovery for which they shared the 2009 Nobel Prize in Medicine.[7] Briefly explained, telomeres are repeating sequences of DNA located at the ends of all our chromosomes. The sequences do not code for any necessary information but are there to protect the rest of the DNA. Think of them as the aglet on the end of a shoelace that prevents the lace from dissolving. When the protective telomeres become too short, the cell will arrest its activity to avoid excessive DNA damage, which could make it turn cancerous.[8]

Some cells, however, have a way of working around this problem. These cells can continuously add more telomere using an enzyme called telomerase. This helps them maintain their telomere length and makes them immortal – at least in theory. Stem cells are the primary users of this mechanism in our bodies.[9] Different kinds of stem cells are distributed in various tissues and tasked with dividing and then differentiating into new cells. For this reason, it makes sense for them to have access to telomerase.  

If a lack of telomeres makes cells mortal, and if telomerase can reverse this, that would seem to imply a quick fix for aging by simply triggering this mechanism in normal cells. It turns out that the matter is not that simple, but more about that later. 

Finally, in the 2000s, British biologist Aubrey de Grey founded Strategies for Engineered Negligible Senescence (SENS), an organization that advocates for life extension, studies aging, and provides funds for anti-aging research. Together with major advances in many subfields of aging research, this has laid the foundation for the surging popularity of anti-aging science.  

It is impossible to give a fair summary of the history of anti-aging research. In the last few decades especially, thousands of people have made meaningful contributions. New scientists are flooding into the field, but so are new entrepreneurs, donors, volunteers, and hobbyists.  

Generally speaking, there are two major challenges involved when we consider the aging process as a disease to be counterbalanced with pharmaceutical drugs (or regenerative medical procedures). First of all, if such drugs are to be taken preventively, they would need to be completely free from side-effects. While adverse side-effects might be considered tolerable in the treatment of severe diseases, they would not be accepted in cases of aging or lifestyle indications.[10]

Secondly, demonstrating the scientific efficacy of anti-aging requires long-term clinical studies that would be both laborious and expensive. The effects of aging on the body take place very slowly (subchronically), making it highly challenging to design scientifically and statistically sound and meaningful clinical studies and to finish them within a timeframe that is manageable and affordable for companies. Because the expected effects are small and slow to evolve, studies need to be large in scale and measure outcomes over many years. This, more than issues surrounding patenting, seems to be a main reason why large pharmaceutical corporations are wary of anti-aging and lifestyle drugs, preferring to focus on more severe and immediate indications, such as diabetic kidney disease. Closely linked to the research effort is the question of whether health insurances would cover preventive anti-aging treatments.

Anti-aging research now encompasses many very different ideas and approaches. We can get an overview in a 2013 paper entitled “The Hallmarks of Aging”.[11] The model presented in this paper is inspired by a similar model for cancer called “The Hallmarks of Cancer”. It describes the different biological alterations thought to play a role in aging. If one of the hallmarks is artificially aggravated in a model organism, aging will accelerate. If it is ameliorated, the organism will live longer. In other words, these hallmarks show us which problems we need to solve.  

V

References

[1] Martin, D.J. and L. Gillen 2014. Revisiting Gerontology’s Scrapbook: From Metchnikoff to the Spectrum Model of Aging. The Gerontologist 54 (1):51-8.

[2] Nagpal, R. et al. 2018. Gut microbiome and aging: Physiological and mechanistic insights. Nutrition and Healthy Aging 4(4):267-85.

[3] McCay, C.M. and M.F. Crowell 1934. Prolonging the Life Span. The Scientific Monthly 39(5):405-14.

[4] Taormina, G. and M.G. Mirisola 2014. Calorie restriction in mammals and simple model organisms. BioMed Research International. Special issue: Aging and Longevity between Genetic Background and Lifestyle Intervention (2014).

[5] Hayflick, L. and P.S. Moorhead 1961. The serial cultivation of human diploid cell strains. Experimental Cell Research 25(3):585-621.

[6] The chromosomes are the structures that contain our DNA. Each of us have 46, 23 from each of our parents.

[7] https://www.nobelprize.org/prizes/medicine/2009/summary/.

[8] Campisi, J. 2000. Cancer, aging and cellular senescence. In Vivo 14(1):183-8.

[9] Cong, Y. et al. 2002. Human telomerase and its regulation. Microbiology and Molecular Biology Reviews 66(3): 407-25.

[10] For an investigation of negative side-effects on post-marketing withdrawals of lifestyle drugs in the pharmaceutical industry, see Onakpoya, I.J. et al. 2016. Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review. BMC Medicine 14:191.

[11] López-Otín, C. et al. 2013. The hallmarks of aging. Cell 153(6): 1194-217.

[213] Kirkwood, T. B. L., and M. R. Rose. 1991. “Evolution of Senescence: Late Survival Sacrificed for Reproduction.” Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 332 (1262): 15–24. https://doi.org/10.1098/rstb.1991.0028.

[214] Partridge, Linda, and Nicholas H. Barton. "Optimally, mutation and the evolution of ageing." Nature 362, no. 6418 (1993): 305-311.

[215] Zwaan, Bas J. "The evolutionary genetics of ageing and longevity." Heredity 82, no. 6 (1999): 589-597.

[216] Medawar, Peter Brian. "Uniqueness of the Individual." In: Medawar, PB An Unsolved Problem of Biology, HK Lewis. 1952.

[217] Williams, George C. "Pleiotropy, natural selection, and the evolution of senescence." evolution (1957): 398-411