Key Takeaways

• STAT Longevity Report notes that recent years mark the beginning of a new era for research on treatments to slow down aging, with multiple ongoing clinical trials testing "the idea that some drugs, by altering the trajectory of fundamental processes inside cells, may delay or even prevent the onset of many diseases of old age."
• The growth of anti-aging research accelerated significantly in 2013, resulting in many breakthroughs between 2013 and 2022. Key directions include "senolytics discovery, drug repurposing, stem cells, genomics, and discovery of biomarkers of aging (‘aging clocks’)."
• In late 2020, researchers from Harvard Medical School managed to turn adult cells to stem cells by using a "harmless virus." In their experiment, old mice with "damaged retinas and poor eyesight" had their vision significantly improved, sometimes to the point where they could see better than their children.

Introduction

Research Into Anti-Aging Treatments

Overall Focus

• Contrary to popular conceptions, the main focus of longevity research is not increasing the lifespan but the healthspan, i.e., how long people can live with no diseases. Jim Mellon, chairman of Juvenescence, a longevity business, notes that a treatment capable of adding one to two years to the healthspan would bring trillions of dollars in global economic benefit, factoring in improved productivity and healthcare-related savings.
• STAT Longevity Report notes that recent years mark the beginning of a new era for research on treatments to slow down aging, with multiple ongoing clinical trials testing "the idea that some drugs, by altering the trajectory of fundamental processes inside cells, may delay or even prevent the onset of many diseases of old age."
• The growth of anti-aging research accelerated significantly in 2013, resulting in many breakthroughs between 2013 and 2022. Key directions include "senolytics discovery, drug repurposing, stem cells, genomics, and discovery of biomarkers of aging (‘aging clocks’)."
• Eric Verdin, CEO of the Buck Institute for Research on Aging, believes that the current knowledge could soon be possible to help people live up to 95 in good health, even though everyone is "only talking about how we are going to get the tech guys to live to 150," which he considers significantly less urgent.

Research Focus in Terms of Aging Hallmark and Indication

• Despite the recent boom in longevity research, none of the treatments in the field have been approved yet, with the first approvals expected no sooner than in 2026.
• Still, longevity research grew significantly between 2011 and 2021. According to Longevity Technology, 2057 papers were published on the topic in 2011, compared to 3991 in 2022. The number of clinical trials by longevity companies went up from 37 to 45.
• These clinical trials can be broken by the aging hallmark they target. 36% of them focus on mitochondrial dysfunction, suggesting that it is among the leading areas of research into treatments to slow down the aging process.
• According to scientists from the Buck Institute for the Research on Aging, the malfunction of the mitochondria of cells occurs in most age-related diseases. They believe that the issue is likely connected to aging in general, stressing that mitochondria play a crucial role in processes such as immune response, metabolism, and inflammation.
• Other areas of focus for clinical trials include stem cell exhaustion (15%), loss of proteostasis (15%), telomere attrition (8%), genomic instability (8%), and senescence (8%).

• In terms of indication, as of 2021, active clinical trials by longevity companies focused on age-related macular degeneration, dementia, obesity, non-alcoholic steatohepatitis, Parkinson's, spinal muscular atrophy, sarcopenia, osteoarthritis, aging frailty, degenerative disc disease, Leber hereditary optic neuropathy, and dry eye disease.
• It is important to note that reports differ in what they classify as aging research clinical trials. The report by Aging Analytics factors in both age-associated disease and longevity clinical trials, which provides a different breakdown by category. However, as seen in the chart below, longevity-focused clinical trials account for about 20%.

 

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• For reference, the regularly updated list of longevity clinical trials is available here.

Recent Discoveries

A Vaccine That Targets Senescent Cells

• In 2021, Japanese scientists achieved a breakthrough in their research into removing senescent cells, i.e., aging cells that can't replicate but, if accumulated, can result in chronic inflammation or disease. They are involved in most age-related diseases and, depending on the place of accumulation, may cause diabetes, heart failure, or other diseases.

 

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• While the role of senescent cells in aging has been studied since 2011, early drugs were not effective in only targeting those "zombie cells," which are neither dead nor alive. They caused serious side effects, as they also killed healthy cells. Similarly, the Tokyo-based group of researchers was initially unsuccessful in identifying the right markers.
• However, in 2021, they identified a protein on the surface of senescent cells, which is so scarce in other types of cells that it can be safely targeted. The discovery served as a basis for developing a vaccine and demonstrating that the immune system can get rid of aging cells with this kind of treatment.
• When used on prematurely aging mice, the vaccine improved the lifespan by 19% while also reducing frailty and metabolic disease.
• The discovery is in the nascent phase and will not be tested on humans for many years. However, the researchers emphasize that other senolytics are already in clinical trials, with the approval of at least one drug from the category expected in the next five years. The full study is available here.

Reprogramming Cells with a "Virus"

• In late 2020, researchers from Harvard Medical School managed to turn adult cells to stem cells by using a "harmless virus." In their experiment, old mice with "damaged retinas and poor eyesight" had their vision significantly improved, sometimes to the point where they could see better than their children. David Sinclair, who led the study, stated that the reversal appeared to be permanent and could be applied to other parts of the body.
• While Dr. Shinya Yamayaka had already reprogrammed human adult cells in 2007 to make them act like stem cells and received a Nobel Prize for his discovery, the reprogrammed cells didn't preserve their identity. Still, his work was an important breakthrough with 'his induced pluripotent stem cells, soon becoming known as Yamanaka factors."
• Further research by scientists from the Salk Institute for Biological Studies led to reprogramming cells without impacting their identity in 2016. However, there was a side effect of some mice developing cancerous tumors.
• Sinclair and his team focused on three out of four Yamanaka factors, unlike the Salk Institute, to increase safety. They were genetically added to a "harmless virus," which was later injected into each mouse's eye. However, researchers noted that the three factors could likely also be delivered in a different form.
• The studies are in the early stages. According to Sinclair, it will be years before clinical trials conclude and such treatment receives FDA approval, with no specific estimation provided. The full study is available here.

Drivers

• Increased adoption of artificial intelligence (AI) and machine learning (ML) is one of the primary drivers of aging research, significantly speeding up the discovery process. According to Biopharma Trend, ML is used to discover new biomarkers, assess biological age, and construct "aging clocks" based on aging phenotypes, as opposed to time.

 

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• AI platforms are used to "enhance the target identification and prioritization process while considering the known molecular aging pathways," as well as clinical trial design and analysis, among others.
• Furthermore, longevity research is driven by large investments, with multiple billionaires either funding existing companies in the space or starting their own initiatives. For example, in 2022, Altos Labs, an aging research initiative, raised $3 billion, with investors including Jeff Bezos, founder of Amazon. In 2021, Brian Armstrong, co-founder of Coinbase, and Blake Byers, venture capitalist, put $105 million into launching a new aging biotech company.
• It is worth noting that according to a 2018 article by CB Insights, funding for longevity companies grew significantly between 2013 and 2018. It's likely that it has been a driver since the boom started in 2013.

 

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Barriers

• However, the investments are largely reserved for companies that are eligible for venture funding (excluding the cases where founders already have enough resources or strong VC networks to back their projects, as explained above). According to Garri Zmudze from Longevity Science Foundation, longevity research is still not fully accepted in the biomedical research space largely due to "the lack of transparent, equity-free funding for early-stage" projects.
• This branch of research also tends to be misunderstood, which contributes to the general lack of acceptance. Media sources tend to promise miracle effects that can be achieved with simple lifestyle changes, even though, in reality, it is a more complex issue "with no silver bullet that will allow humanity as a whole to live longer."
• A research paper published in the Frontiers in Aging notes that most breakthrough discoveries require significant research before it can be determined how they translate to humans. However, clinical trials in the longevity space are problematic, as it is not feasible or practical to target a longer lifespan as the primary outcome, so they always need surrogate biomarkers.

Research Strategy

Key Takeaways

• The study titled "Longitudinal analysis of blood markers reveals progressive loss of resilience and predicts human lifespan limit" was published on May 25, 2021, in Nature Communications. The study revealed that even under ideal biological circumstances, the biomarkers of aging would show so much decline by 150 years of age that a living organism could not be supported. Hence, the maximum age limit of a human being under ideal circumstances is 150 years.
• The study titled "Distinct designer diamines promote mitophagy, and thereby enhance healthspan in C. elegans and protect human cells against oxidative damage" was published on June 1, 2022, in Autophagy, a peer-reviewed scientific journal. In the study, the researchers were successfully able to identify "a group of molecules that enable cells to repair damaged components, making it possible for those tissues to retain proper function." These molecules have the ability to potentially prevent and also treat major age-related diseases like Alzheimer's and Parkinson's.
• The study titled "Mendelian randomization analyses implicate biogenesis of translation machinery in human aging" was published on January 25, 2022, in Genome Research, a peer-reviewed scientific journal. The researchers found that people in whom the activity of certain genes was reduced had an increased likelihood of living longer lives compared to their peers. These "genes are linked to two RNA polymerase enzymes (Pols) that transcribe ribosomal and transfer RNAs, namely Pol I and Pol III, as well as the expression of ribosomal protein genes."
• The study titled "Impact of modifiable healthy lifestyle adoption on lifetime gain from middle to older age" was published on May 11, 2022, in Age and Ageing, a peer-reviewed medical journal. The purpose of the study was to explore the correlation between lifestyle modification and "life expectancy from middle age onwards, regardless of the presence of major comorbidities."

Introduction

"Longitudinal Analysis of Blood Markers Reveals Progressive Loss of Resilience and Predicts Human Lifespan Limit"

• The study titled "Longitudinal analysis of blood markers reveals progressive loss of resilience and predicts human lifespan limit" was published on May 25, 2021, in Nature Communications.
• The team of researchers led by Timothy V. Pyrkov are affiliated with the following institutions: Gero PTE, Singapore; Skolkovo Institute of Science and Technology, Moscow; Moscow Institute of Physics and Technology, Dolgoprudny, Russia; National Research Center ‘Kurchatov Institute’, Moscow; Roswell Park Comprehensive Cancer Center, Elm and Carlton streets, Buffalo, New York; and Genome Protection, Inc., Buffalo, New York.
• To identify the maximum age limit of a human being, the researchers analyzed anonymized blood samples belonging to 544,398 people in the US, UK, and Russia. The researchers evaluated the individual's log-linear mortality estimate called dynamic organism state indicator (DOSI) from two parameters: the variability in the red blood cell sizes and the ratio of two white blood cell types used by the immune system to fight infection.
• The researchers calculated the maximum age limit of a human being by plugging the above biomarkers of aging and other basic medical data belonging to each volunteer like the number of steps taken daily into a computer model.
• The computer model revealed that "DOSI recovery time and variance would simultaneously diverge at a critical point of 120 − 150 years of age corresponding to a complete loss of resilience." This means that even under ideal biological circumstances, the biomarkers of aging would show so much decline by 150 years of age that a living organism could not be supported. Hence, the maximum age limit of a human being under ideal circumstances is 150 years.

 

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• The study also revealed that with age, the human body takes more time to recover from stress conditions since "the body’s response to insults could increasingly range far from a stable normal."

"Distinct Designer Diamines Promote Mitophagy, and Thereby Enhance Healthspan in C. Elegans and Protect Human Cells Against Oxidative Damage"

• The study titled "Distinct designer diamines promote mitophagy, and thereby enhance healthspan in C. elegans and protect human cells against oxidative damage" was published on June 1, 2022, in Autophagy, a peer-reviewed scientific journal. However, the paper is behind a paywall and its viewing requires a purchase of the same.
• The team of researchers led by Einav Gross and Shmuel A. Ben-Sasson are affiliated with The Hebrew University of Jerusalem, Israel.
• Currently, a major reason for the aging of tissues is the "reduced effectiveness of the cell's quality-control mechanism, which leads to the accumulation of defective mitochondria." According to Gross, mitochondria are the cell's power plants and are comparable to minuscule electric batteries. They are responsible for the production of energy and help the cells to function properly. Although the mitochondria deplete constantly, the cell's mechanism helps to remove defective mitochondria and replace them with new ones. However, advancing age causes the decline of this cell mechanism, "leading to cell dysfunction and deterioration in tissue activity."
• The above-mentioned degenerative process is responsible for several age-related diseases like Alzheimer's, Parkinson's, sarcopenia, and heart failure. In the study, the researchers were successfully able to identify "a group of molecules that enable cells to repair damaged components, making it possible for those tissues to retain proper function." These molecules have the ability to potentially prevent and also treat major age-related diseases like Alzheimer's and Parkinson's.
• The researchers demonstrated the efficacy of the molecules on a model organism. They also "examined the effect of various therapies on longevity and quality of life, and successfully proved they can protect the organism's and human cells from damage." Using the identified molecules, the researchers are currently developing a drug candidate that has the potential to expand the longevity of human beings.
• Together with Yissum, the university's technology transfer company, the researchers have established Vitalunga, a startup responsible for developing the drug. According to Prof. Ben-Sasson, Vitalunga has set a target of completing preclinical preparations in two years and commercial delivery of the drug within five years.

"Mendelian Randomization Analyses Implicate Biogenesis of Translation Machinery in Human Aging"

• The study titled "Mendelian randomization analyses implicate biogenesis of translation machinery in human aging" was published on January 25, 2022, in Genome Research, a peer-reviewed scientific journal.
• The team of researchers led by Nazif Alic and Karoline Kuchenbaecker are affiliated with the following institutions: University College London, University of Glasgow, and University of Kent. The study was funded by Wellcome and the Biotechnology and Biological Sciences Research Council.
• In the study, the researchers reviewed previous scientific studies and found genetic data for "11,262 people who had lived an exceptionally long life, to an age above the 90th percentile of their cohort."
• The researchers found that people in whom the activity of certain genes was reduced had an increased likelihood of living longer lives compared to their peers. These "genes are linked to two RNA polymerase enzymes (Pols) that transcribe ribosomal and transfer RNAs, namely Pol I and Pol III, as well as the expression of ribosomal protein genes."
• Besides finding evidence that the genes affected the functioning of organs like skeletal muscle, liver, and abdominal fat, the researchers also found evidence that the genes were linked to human longevity. However, these genes have been classified under the example of antagonistic pleiotropy, wherein they facilitate the protein synthesis mechanism of cells in the early years but are not as useful in advanced age. Dr. Nazif Alic said, "Here, we have found that inhibiting these genes may also increase longevity in people, perhaps because they are most useful early in life before causing problems in late life."
• The findings of the study have added to the evidence that drugs like rapamycin, a Pol III inhibiting immune regulator, could increase the lifespan in humans.

"Impact of Modifiable Healthy Lifestyle Adoption on Lifetime Gain From Middle to Older Age"

• The study titled "Impact of modifiable healthy lifestyle adoption on lifetime gain from middle to older age" was published on May 11, 2022, in Age and Ageing, a peer-reviewed medical journal.
• The team of researchers led by Dr. Ryoto Sakaniwa is associated with the Japan Collaborate Cohort (JACC) Study group at Osaka University. The study was supported by the Nagoya University School of Medicine.
• The purpose of the study was to explore the correlation between lifestyle modification and "life expectancy from middle age onwards, regardless of the presence of major comorbidities."
• In the study, the researchers examined the respective lifestyles and medical histories of 49,021 Japanese people (21,453 men and 27,568 women) aged 40-79 years in 45 communities across Japan through a common questionnaire between 1988 and 1990. The questionnaire contained questions on several components of a healthy lifestyle, including diet, sleep duration, walking/exercise, smoking status, body mass index (BMI), and alcohol consumption. One point was awarded for each modifiable healthy lifestyle factor, and the impact of making lifestyle changes on the expected lifetime was analyzed.
• The study was conducted till December 2009, and 8,966 participants died during the interim. The study revealed that modifiable healthy lifestyle adoption was directly related to increased longevity in both men and women. According to Dr. Ryoto Sakaniwa, "The results were very clear. A higher number of modified healthy behaviors was directly associated with great longevity for both men and women." The study showed that making healthy lifestyle changes like losing weight, increasing sleep, not smoking, and reducing alcohol consumption had the potential of adding 6 years to the lives of healthy 40-year-olds.

 

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• The study also revealed that making healthy lifestyle changes had the potential of increasing the lifespan of older individuals aged 80 years and above, "regardless of the presence of any major comorbidities in each life stage since middle age." These comorbidities include cancer, diabetes, hypertension, kidney disease, and cardiovascular disease.

 

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Research Strategy