9. Genomic Instability

Each of our cells contains our entire genome at its core.^[176] This consists of 3 billion bases arranged into 23 chromosomes, and each cell has two “sets” – one from each of our parents. One may think of it as a book with 6 billion letters.

When the cell divides, both daughter cells need a copy of all of this information. Before the cell can do so, it will thus copy its entire genome. Mistakes could be lethal to the daughter cell, could make it into a cancer cell, or could slowly accumulate and make future daughter cells ever more dysfunctional. 

Through its lifespan, a human body experiences 10 quadrillion cell divisions, and in all of these, the 6 billion base pairs have to be copied correctly.^[177] This number is astronomical. Even a small error rate would quickly render our cells littered with errors.

The enzyme that replicates our DNA has an error rate of 1 per 100.000 bases. That might sound small, but would amount to 120.000 mistakes per cell division. Fortunately, we have sophisticated machinery to correct these mistakes. Some are corrected in what is called proofreading, which fixes almost all mistakes. Later, another mechanism called mismatch repair fixes most of the remaining mistakes.^[178]

Despite all of this, errors do occasionally become permanent. This is called a mutation. In humans, there is often less than one mutation per cell division.^[179] Imagine copying a book of 6 billion letters letter by letter and then only making a single mistake throughout. This is very impressive, but means that we do accumulate mutations.

Besides errors during replication, DNA is also constantly threatened by chemical reactions in the cells, environmental influence, infections with viruses, and relocation of transposons (jumping genes).^[180] There are more than 10.000 cases of oxidative damage per cell per day, for instance.^[181] Most will be fixed, but once again, a gradual accumulation of mutations is unavoidable.

Mutations in our cells are not only point-mutations, caused by the change of a single base (“letter”) to another, but can also be insertions, deletions, duplications, inversions, and translocations of stretches of DNA.  

Cells are very complex, and changing anything in a complex system is generally a bad idea – especially when it is not damaged. For this reason, mutations are seldom a good thing. Most often, they are neutral, but sometimes they are bad for us. They might decrease the functionality of the cell or lead it one step closer to becoming cancerous. 

Theoretically, therefore, it makes sense that an accumulation of DNA mutations would weaken us with age. However, we also have proof from the real world. We know of several syndromes where the affected people age rapidly. Most of these are in some way related to the integrity of our DNA, and the affected people’s DNA damage accumulates.^[182] Mice with defective DNA repair also show accelerated aging.^[183]

Mutations and DNA repair are permanent, and it would be extraordinarily difficult to fix them artificially. The best bet is to stop them from happening in the first place, but even this is difficult. Certain lifestyle choices, such as not smoking, help greatly. However, all people experience an accumulation of mutations with age.^[184] It is possible that certain drugs would be able to decrease the amount of damage to our cells. As we know, some kinds of damage are beneficial, though, and any therapy would have to take this into account.

Most mutations are repaired and therefore are not harmful – some are in non-important areas, some are so-called synonymous mutations, meaning they do not change the proteins they code for, and some have no effect even though they do cause a change. The mutations we need to target are the ones causing dysfunction of the cell. The body has its own mechanisms for this. Dysfunctional cells will often undergo apoptosis (cellular suicide) and thus cease to be a problem. Some will also become senescent, and approaches to removing these are already under development. Some avoid these mechanisms and become cancerous. Once again, progress in oncology is likely to stimulate advances in this area. 

What is left after taking all this into account are the mutations that cause a slight decrease in functionality, but not enough to trigger apoptosis or senescence. It is conceivable that this type of mutation can accumulate and lead to a gradual weakening of cell functionality. The most promising approach is to find a way to avoid these mutations altogether, as determining mutations in single cells or small populations and inferring their effect would be close to impossible.  

We can consider cancer as a disease of the genome. As mutations, and thus the likelihood for acquiring many cancer types increases by age, it is obvious that longevity will be accompanied by an increase in cancer (all age-related cancer statistics point towards this fact). Since cancer and anti-cancer drugs are a huge field in their own right, we will not cover this connection in depth for the purposes of the present report. 

Ponce De Leon Health^[241]

Website https://pdlhealth.com/

Industry Consumer Goods

Company Size 2-10 employees

Headquarters Fernandina Beach, Florida

Type Privately Held

Funded 2014

Ponce De Leon’s research aims at developing and commercializing a safe, affordable, science-backed, non-drug product for a longer and healthier life. The company’s initial efforts were conducted in collaboration with the Buck Institute for Research on Aging. By screening over 300 Generally Recognized As Safe formulations, the Buck Institute’s scientific team was able to modulate the pathways associated with healthy aging in mammals. Initial targets included mTOR inhibition, blocking inflammatory cytokines of senescent cells, DNA integrity, ammonia detoxification and protein homeostasis. 

Underdog Pharmaceuticals^[242]

Website https://underdogpharma.com/

Industry Biotechnology

Company Size 2-10 employees

Headquarters Mountain View, California

Type Privately Held

Funded 2019

This company plans to treat the underlying causes of age-related disease through simple and direct interventions targeting toxic forms of cholesterol, using rationally designed molecules, to provide the first true disease-modifying treatments for age-related diseases such as atherosclerosis, hypercholesterolemia, heart failure, and macular degeneration. A SENS Research Foundation program supports Underdog’s efforts to develop novel derivatives of well-known, safe compounds and a new way of looking at cardiovascular disease.

The list of hallmarks of cancer has been expanded since it was originally formulated, and it is likely the hallmarks of aging will be as well. Currently, most scientists are working on one of the nine currently identified hallmarks, but some are also searching for new phenomena in aging. It has become especially popular to include artificial intelligence (AI) in this search. The AI boom in longevity research took off in the beginning of the 2010s and has since accelerated, with multiple companies entering the scene recently. Scientists hope that machine-learning algorithms will be able to spot new patterns in cells and model organism that can give us new clues on why we age. Traditional lab experiments are obviously crucial, but they are slow to conduct and very expensive. By using AI methods on existing and new datasets, the process of discovery can be accelerated. 

Insilico Medicine^[188]

Website http://www.Insilico.com 

Industry Biotechnology 

Company size 11-50 employees 

Type Privately Held 

Founded 2014 

Insilico Medicine was founded by Alex Zhavoronkov in 2014. Its stated mission is to use AI for drug discovery and aging research to extend healthy longevity. Through its PharmaAI division, it provides machine-learning services to many large companies. The company itself has more than 150 collaborators in academia and industry. Though Insilico Medicine is a quite young company, it has already amassed a large amount of valuable data, for instance from various tissues and cell types of different ages. Its researchers have also published many papers in the most prestigious international journals.^[189]For this reason, Insilico Medicine has attracted significant attention from investors, raising money from Juvenescence and Deep Knowledge Ventures, among others.^[190]

Spring Discovery^[191]

Website https://www.springdisc.com/ 

Industry Biotechnology 

Company size 2-10 employees 

Headquarters Palo Alto, California 

Type Privately Held 

Founded 2017 

Spring Discovery was founded by engineer Ben Kamens, and employs both machine learning and aging biology experts. The company has the long-term mission of using an AI-driven approach to discover new treatments for age-related diseases and aging itself. To reach its goal, it has developed a novel machine-learning platform. The company received US$18 mn in Series A funding led by First Round and General Catalyst. Other investors include the Longevity Fund.^[192]

Human Longevity Inc^[193]

Website http://www.humanlongevity.com 

Industry Biotechnology 

Company size 51-200 employees 

Headquarters San Diego, CA 

Type Privately Held 

Founded 2013 

Human Longevity Inc was founded by Craig Venter and Peter Diamandis in 2013. In the 1990s, Venter led the company Celera Genomics, which sequenced the human genome for the first type.^[194] Diamandis is a well-known serial entrepreneur, having founded the X PRIZE Foundation and Singularity University, among other ventures. The goal of Human Longevity is to build a large database on human geno- and phenotypes and to apply machine learning to this data to discover cures. To get the data, the company offers a wellness service called the Health Nucleus. This is a comprehensive medical examination containing extensive blood work, whole-body scanning, full genome sequencing, and microbiome tests. The service aims at discovering early signs of age-related disease (especially cancers) at a stage when they are still harmless and can be treated.

BioAge Labs^[195]

Website http://bioagelabs.com/ 

Industry Biotechnology 

Company size 11-50 employees 

Headquarters Richmond, CA 

Type Privately Held 

Founded 2015 

BioAge Labs was founded by Kristen Fortney and Eric Morgen. The company has built a systems biology and AI platform with blood data from 600 long-lived Estonians as well as numerous lab mice. It uses this platform to discover new drugs for life extension. The first target identified by the company is the hypoxia-inducible factor pathway. It has obtained an exclusive license to develop and commercialize a specific inhibitor called BGE-117.^[196] BioAge Labs raised US$10.9 mn in Series A financing led by Andreeseen Horowitz Bio Fund^[197] and US$23 mn in Series B financing led by Felicis Ventures.^[198]

Gero^[199]

Website http://gero.ai/ 

Industry Biotechnology 

Company size 11-50 employees 

Headquarters Сингапур, Singapore 

Type Privately Held 

Founded 2015 

Gero was founded in 2012 by Peter Fedichev and Maxim Kholin with the aim of applying AI to longevity research and drug development. The company works on several experimental therapies and has demonstrated the ability to reduce the biological age of mice. It has also identified new compound with potential in other model organisms and developed the iOS app Gero Healthspan.^[200]

There are a number of life extension companies active in the market whose approach does not tackle one of the nine hallmarks of aging listed above. As seen in the section “AI”, a lot of these companies are using artificial intelligence to boost drug discovery and development. Others operate in areas such as venture capital, supplements and new developmental approaches. In the following, these companies are briefly portrayed. 

Calico^[201]

Website http://www.calicolabs.com/ 

Industry Biotechnology 

Company size 201-500 employees 

Headquarters South San Francisco, CA 

Type Privately Held 

Founded 2013 

Calico (California Life Company) is a spinout of Google (now a subsidiary of Alphabet Inc.) founded by Bill Marris, who also founded Google’s venture capital arm Google Ventures. The company is engaged in R&D aiming to increase our understanding of aging and devise interventions. Several world-leading aging experts are employed at Calico, but the company is very secretive, and no concrete information is available about its projects. 

Juvenescence^[202]

Website https://www.juvenescence.ltd 

Industry Biotechnology 

Company size 2-10 employees 

Headquarters Douglas, Douglas 

Type Privately Held 

Founded 2016 

Juvenescence is a venture capital firm focusing on human longevity. It was founded by British businessman and biotech investor Jim Mellon. In 2018, the company raised US$50 mn in Series A financing^[203] and US$100 mn in a Series B round.^[204] It is planning an IPO for the second half of 2020.^[205] Among its investments are AgeX Therapeutics and Insilico Medicine.

The Longevity Fund^[206]

Website http://longevity.vc 

Industry Biotechnology 

Company size 2-10 employees 

Headquarters San Francisco, California 

Type Privately Held 

The Longevity Fund is a Silicon Valley venture capital firm exploring human longevity. It was founded by young venture capitalist Laura Deming and raised US$4 mn in its first funding round and US$22 mn in its second fund.^[207] Among the companies backed by The Longevity Fund are Unity Biotechnologies, Spring Discovery, and Gordian Biotechnologies.

Gordian Biotechnologies^[208]

Website http://www.gordian.bio 

Industry Biotechnology 

Company size 2-10 employees 

Headquarters San Francisco, California 

Type Privately Held 

Founded 2018  

Gordian Biotechnologies was founded in 2018 by a group of scientists who are working to develop a discovery platform that makes it possible to conduct efficacy testing in aged tissues. Many studies are currently being conducted based on unrealistic models, such as immortal cell lines or young mice. Gordian’s technology could change this and help improve the testing of life extension interventions. 

Life Extension^[209]

Website https://www.lifeextension.com/ 

Industry Alternative Medicine 

Company size 201-500 employees 

Headquarters Ft. Lauderdale, FL 

Type Privately Held 

Founded 1980 

Life Extension is a vitamin and supplements company. It carries a long list of supplements aimed at fighting all the major age-related diseases as well as the aging process itself. Furthermore, it offers a wide range of lab tests for everything from heart health to metabolism, immune health, hormonal balance, and many other aspects of the human body.  

[176] Except red blood cells.

[177] ”Number of cell divisions in an average human lifespan”. https://bionumbers.hms.harvard.edu/bionumber.aspx?id=100379 (last accessed 6 August 2020).

[178] Pray, L.A. 2008. DNA replication and causes of mutation. Nature Education 1(1):214.

[179] Lynch, M. 2010. Evolution of the mutation rate. Trends in Genetics 26(8): 345-52.

[180] Hoeijmakers , J.H.J. 2009. DNA damage, aging, and cancer. New England Journal of Medicine 361(15):1475-85.

[181] Helbock, H.J. 1998. DNA oxidation matters: The HPLC–electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine. Proceedings of the National Academy of Sciences of the USA 95(1): 288-93.

[182] Burtner, C.R. and B.K. Kennedy 2010. Progeria syndromes and ageing: what is the connection? Nature Reviews Molecular Cell Biology 11(8):567-78.

[183] Gregg, S.Q. et al. 2012. A mouse model of accelerated liver aging caused by a defect in DNA repair. Hepatology 55(2):609-21.

[184] Moskalev, A.A. et al. 2013. The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Research Reviews 12(2):661-84.

[185] https://www.humanlongevity.com/

[186] This company is also listed in the section on AI. There are only few, if any, anti-aging companies working on genomic instability

[187] In parallel with the publicly funded Human Genome Project.

[188] https://insilico.com/

[189] https://insilico.com/publications

[190] Hale, C. "Insilico raises $37M with plans to bring its AI to more drug discovery partnerships”. Fierce Biotech, 12 September 2019. https://www.fiercebiotech.com/medtech/insilico-raises-37m-plans-to-bring-its-ai-to-more-drug-discovery-partnerships (last accessed 6 August 2020).

[191] https://www.springdiscovery.com/

[192] Kamens, B. "With $18 million in new funding, Spring is speeding up our engine for discovering aging therapies”. Spring Discovery, 11 December 2018. https://medium.com/spring-discovery/with-18-million-in-new-funding-spring-is-speeding-up-our-engine-for-discovering-aging-therapies-c2ea6ff7d330 (last accessed on 6 August 2020).

[193] https://www.humanlongevity.com/

[194] In parallel with the publicly funded Human Genome Project.

[195] https://bioagelabs.com/

[196] "BioAge Signs Exclusive License Agreement with Taisho to Develop and Commercialize Taisho’s Phase 1 HIF-PH Inhibitor to Treat Aging". BioAge Labs, 29 April 2020. https://bioagelabs.com/BioAge_Taisho.pdf (last accessed 13 August 2020).

[197] ”BioAge Labs raises $10.9M in Series A financing to accelerate drug discovery for aging”. BioAge Labs, 24 January 2019. https://medium.com/@BioAge/bioage-labs-raises-10-9m-in-series-a-financing-to-accelerate-drug-discovery-for-aging-31974fcb3229 (last accessed 6 August 2020).

[198] ”BIOAGE raises $23M to scale AI-driven platform to discover and develop drugs that treat aging”. BioAge Labs, 24 January 2019. https://medium.com/@BioAge/bioage-raises-23m-to-scale-ai-driven-platform-to-discover-and-develop-drugs-that-treat-aging-176eaed36efa (last accessed 6 August 2020).

[199] https://gero.ai/

[200] https://www.crunchbase.com/organization/gero#section-overview

[201] https://www.calicolabs.com/

[202] https://juvenescence.ltd/

[203] Terry, M. ”Juvenescence Closes on Series A Financing Worth $50 Million to Focus on Human Longevity”. BioSpace, 12 June 2018. https://www.biospace.com/article/juvenescence-closes-on-series-a-financing-worth-50-million-to-focus-on-human-longevity/ (last accessed 6 August 2020).

[204] ”Juvenescence Closes $100 Million Series B Round, Plans Follow on and Incremental Investments in Longevity Drug Development”. BusinessWire, 19 August 2019. https://www.businesswire.com/news/home/20190818005019/en/Juvenescence-Closes-100-Million-Series-Plans-Follow (last accessed 6 August 2020).

[205] Newman, P. ”Juvenescence moves IPO to second half of 2020”. Longevity Technology, 8 October 2019. https://www.longevity.technology/juvenescence-moves-ipo-to-second-half-of-2020/ (last accessed 6 August 2020).

[206] https://www.longevity.vc/

[207] Loizos, C. ”This 23-year-old just closed her second fund — which is focused on aging — with $22 million”. TechCrunch, 22 August 2017. https://techcrunch.com/2017/08/22/this-23-year-old-just-closed-her-second-fund-which-is-focused-on-aging-with-22-million/ (last accessed 6 August 2020).

[208] https://www.gordian.bio/

[209] http://www.lifeextension.com/

[241] https://pdlhealth.com/

[242] 242 https://underdogpharma.com/