14 min read

Rejuvenation Technology - Aging, Anti-aging and Zombie Cells

Abstract: A human lifespan is like the flickering of a firefly on the scale of the universe. For almost the entirety of human history, average life spans circled around 35 years, long enough to reproduce and nurture children. It was only at the dawn of the 20th century, with advances in modern biotechnology, did we start seeing a rapid increase in average lifespans. Advances in longevity research could mean we could live longer healthier lifespans in the near future.

Introduction

A Brief History of Biotechnology:

If one googled the term biotechnology, the results will yield the definition as a technology that utilizes biological systems, living organisms or parts of this to develop or create different products. Usually, in food and medicine, antiquity dates back to 5000 BC when Egyptians used yeast to brew beer and to bake bread. (Yes, you can enjoy your favourite bread and beer thanks to biotechnology.) Even around 1500 BC, rulers have sent plant-collectors to gather prized exotic genetic resources such as the Queen of Egypt sent a team to regions around modern Somalia and Ethiopia to gather specimens of plants that produced valuable frankincense(tea).

Biotech, for the most part of history, has been accidental discoveries or random uneducated guesses until the Enlightenment era where science and namely, the quest for good explanation gave way to rapid advances. Charles Darwin’s theory of natural selection and subsequently Gregor Mendel’s conjecture that there were 'units of heredity' - later called genes - gave rise to genetic applications such as cross-breeding that allowed for improved crop efficiency.

One of the two most famous stories in the field of biotechnology is the accidental discovery of penicillin in 1928, a group of antibiotics, which changed the course of medicine. During Alexander Fleming’s vacation, a mould had developed on an accidentally contaminated bacterium in his lab and upon close observation, the mould prevented further growth of the bacterium. And voila, you got antibiotics.

The second being the Haber-Bosch process, artificial nitrogen fixation process which is the source of nitrogen/ammonia that acts as nutrients in plant metabolism. This helped the world to overcome the need for seagull droppings as the source of fertilizer and create synthetic fertilizers that have been staving off many potential famines and feeding the world.

However, the most important transformation in the field of biotech occurred with the discovery of the double-structure of DNA. Humans, herbs and horses share virtually the same DNA but differ only in the precise structuring of the chemical bases in DNA. This discovery enabled genetic engineers to conclude that life forms could be edited and modified.

The Human Genome project began in the early 1990s to synthesize(read) DNA. What started at 100 Million $ to read a genome sequence costs less than a 1000$ today. In other words, the cost has fallen at a much faster pace than Moore’s law. With CRISPR(clustered regularly interspaced short palindromic repeats), we have started entering the sequencing(write) mode. Just as computers are programmed to manipulate data, CRISPR enables one to programme cells to manipulate matter.

Although the evolution rate of synbio is much faster than semiconductors(Moore’s law), the biotech industry is heavily regulated and takes a lot of time to clear trials. This makes it a much slower process. Unless (i)regulations are carefully relaxed, (ii)regulatory bodies are made more competent and (iii)technological advances are made in a way that minimizes risk while accelerating the ability to successfully clear parallel clinical trials - as in the case of covid, the innovation scope is limited in biotech.

Why aging?

Clearly, there are both philosophical and technological questions surrounding whether aging is a disease and if yes, can and should it be treated?

The core purpose of rejuvenation biotechnology is not curing death but rather increasing the healthy lifespan of a human. In other words, compressing morbidity and pushing it to the final stages of human lives. On a practical level, delayed aging means having a younger body and mind than the majority of today’s chronological age and spending a larger proportion of life in good health and free from frailty as well as disability. Extended lifespan will be a logical consequence of being healthy.

Credits: rejuvantvip.com

The technological or biological point of view is that competing causes of death are more directly associated with biological aging (e.g., heart disease, cancer, stroke, Alzheimer’s, etc.). Even for Covid, aging and age-related diseases are the biggest risk factors. Naturally, tackling aging could cure most of these conditions. Rather than addressing one disease after another, tackling them one go isa gateway to longer and healthier lifespans. From an economic standpoint of view, delayed aging is an economically positive solution. Pension costs, age-related healthcare economic burden can all be brought down with delayed ageing.

The fear that if we extend the lifespans of human lives, the world might become overpopulated is a rather false narrative. The bigger worry should rather be underpopulation. As already seen in developed economies, extended lifespan and prosperity have already delayed adults from having children and reduced the no. of children. While extending life spans will only further delay child-bearing, it is a different problem to address on a different day. However, if you’d like to read an in-depth ethical aspects of immortality(in case we get there), you can read here.

Nevertheless, David Sinclair in his book claims we won’t be able to find an aging gene. Unlike oncogenes - a good target to battle against cancer, there is no singular gene for aging because our genes did not evolve to cause aging. To understand rejuvenation biotechnology, certain basic keywords must be kept handy.

(Glad to do this favour for you but if you don’t want to be schooled, you can skip the following section. Had to school myself.)

Technical Landscape

Some basic terminologies and functions:

Amino acids are organic compounds(made of mostly Carbon, Hydrogen, Oxygen and Nitrogen) that combine to form proteins which help the body in breaking down food.

Protein folding is the process that occurs inside cells by which a protein structure assumes its functional shape. Unfolded or misfolded proteins contribute to the pathology of many diseases.

Cells, the basic building blocks of all living things, provide structure for the body, contain instructions(remember this) and carry out specialized functions. Every normal human cell contains 23 pairs of chromosomes. Chromosomes are structures within cells that contain a person's genes. Chromosomes have protective caps at each end called Telomeres. Repeated thousands of times, the sequence both prevents the chromosomes from being damaged and controls the number of replications a cell can make, acting as a clock. Mitochondria are miniature factories, acting as powerhouses of cells, which convert food into usable energy in the form of a chemical called adenosine triphosphate (ATP).

Credit: Mirakind.org

Genes are made of chemicals called deoxyribonucleic acid or DNA (a double helix i.e, two long, thin strands twisted around each other like a spiral staircase) that contain the code for a specific protein that functions in one or more types of cells in the body. Genes contain the information needed to make (or sometimes assemble) functional molecules called proteins.

A Base is a unit of the DNA. There are 4 bases: adenine (A), guanine (G), thymine (T), and cytosine (C). The sequence of bases (for example, CTG or CAG) is the genetic code.

The journey from gene to protein is called gene expression and it occurs in two stages: transcription and translation. At the first step of transcription, the information stored in a gene's DNA is transferred to RNA (ribonucleic acid) in the cell nucleus. Called the messenger RNA (mRNA), it carries the information(to make proteins) from the DNA out of the nucleus into the cytoplasm(region inside the cell excluding the nucleus).

Translation, the second step in getting from a gene to a protein, takes place in the cytoplasm. Ribosome is a specialized complex inside the cytoplasm that interacts with the mRNA to read the sequence of mRNA bases. Each sequence of three bases is called a codon that usually codes for one particular amino acid. The transfer RNA (tRNA) then assembles the protein, one amino acid at a time. Protein assembly continues until the ribosome encounters a “stop” codon.

The genome(or genotype) is a person’s unique combination of genes or genetic makeup. An epigenome consists of a record of the chemical changes to theDNA andcertain proteins of an organism; these changes can be passed down to an organism's offspring. Changes to the epigenome can result in changes to the function of the genome. Unlike the genome, which remains largely static within an individual, the epigenome can be dynamically altered by environmental conditions.

Stem cells arise from the earliest cell lineage that can differentiate into different types of cells and then proliferate indefinitely to produce more of the same cell.

Senescent cells do not divide or support the tissues of which they are part; instead, they emit harmful chemicals that encourage nearby healthy cells to enter the same senescent state. Senescent cells play an important role in the biological function of the body by managing repair in the wound healing process. Ideally, the immune system clears the senescent cells after the healing process is complete but with ageing, this ability gets tampered aka they remain as zombie cells.

Hallmarks of Aging:

Just like human information technology, there are two types of information in biology:

a) digital i.e genetic information, the nucleotides A,T,G,C of DNA

b) analog i.e epigenetic information; epigenetics is the study of changes in gene expression

If the genome is the computer, then epigenome is the software that instructs the newly divided cells on what type of cells they should be and what function they should perform. Eg: Differentiation between nerve cells and kidney cells. Since they are analog information, they get easily degraded over time due to factors such as magnetic fields, gravity, cosmic rays, oxygen, loss of information while copying. As epigenetic information gets degraded with age, cells start to lose their identities and lead to all sorts of age-related diseases. Or in other words, aging is the result of the epigenetic changes scrambling how the body reads genetic code.

Degradation of digital information also occurs with aging.

There are currently 9 major hallmarks of aging, mostly targeting digital information and one based on analog information:

  1. Cellular Senescence:

Since senescent cells(zombie cells) accumulate with age encouraging other cells to also become senescent, one of the highly active fields in the rejuvenation biotech industry is removal of these cells. The therapeutic removal of senescent cells to delay or prevent age-related diseases has attracted the birth of so many startups. After successful results in mice, the trial is being translated to humans.

2. Genomic Instability:

DNA contains the blueprints for cells in our bodies to produce proteins and other essential materials. Hence, the DNA is vital to functional and survival. Damages occur to DNA regularly but they accumulate over time as we grow. DNA damage affects the function of stem cells, compromising the supply of replacement cells for tissue renewal. As we age, accumulation of DNA damages lead to cancer and congenital disorder. Voila, another reason to fight against aging/find ways to repair our genes.

3. Epigenetic Alterations:

Remember gene expression(digital)? Epigenetic alterations(analog) are changes to gene expression that our cells experience as we get older, leading to cancer and other age-related diseases. Just like a program in a computer can be reset based on instructions, reprogramming factors can potentially reset age-related epigenetic alterations. Scientists at Harvard Medical School have successfully restored age-related vision loss through epigenetic alterations in mice.

4. Telomere attrition:

The gradual loss of the protective caps of chromosomes limits the number of times cells can divide, and thus leading to dwindling populations of cells in vital organs with age. Research at Salk institute has shown that reprogramming factors to reset the epigenetic alterations also extend the length of telomeres. Restoring telomeres in specific target cells through therapies and replacing senescent cells with stem cells are other solutions to tackle telomere attrition.

5. Loss of Proteostasis:

Loss of proteostasis is the failure of the protein building function of the cell and the accumulation of misfolded proteins( root causes of age-related diseases, such as Alzheimer’s). Current research in addressing the loss of proteostasis includes, among many others, increasing DNA repair, genome repair and proteostasis-regulating drugs.

6. Mitochondrial Dysfunction:

Mitochondria becomes dysfunctional with age reducing the ability to provide chemical energy.

As we age, our mitochondria go through changes that harm their ability to provide us with chemical energy releasing harmful reactive oxygen species - which mutate DNA leading to cancer, harmproteostasis, drive muscle weakness, smolder inflammage, cause bone frailty, increase senescent cell load and immune suppression of old age. Pheww! Almost the entirety of aging related problems. One of the research focuses at SENS research foundation is about developing MitoSENS that engineers a system to prevent harm caused by mitochondrial mutation.

7. Deregulated Nutrient Sensing:

Four key proteins are involved in nutrient sensing, of which 2 when increased in concentration and the other 2 when decreased in concentration promote longevity. Working in contrasts, regulating nutrient levels can influence the concentration level of these proteins.

8. Stem Cell Exhaustion:

responsible for many of the physical problems associated with aging, such as frailty and a weakened immune system, they are either influenced by senescent cells or through direct damage and destruction such as telomere shortening. Thus, solutions for senescent removals and telomere attritions should work here.

9. Altered Intercellular Communication:

Changes in communication signals between cells can lead to some age-related diseases. The root cause of this hallmark is related to other hallmarks and particularly cellular senescence.

Market Landscape

Credits: Biopharmatrend.com

The way forward:

  1. Senescent Cells:

It is clear that removal of senescent cells can impact multiple hallmarks and for that exact reason, there are multiple research labs and longevity startups focused on Senolytics which is about developing solutions to removing senescent cells.

There are 3 fundamental approaches to tackling senescent cells. The first of which is by using Senolytic drugs designed to treat aging by eliminating senescent cells. It is still unclear whether or not senescent cells need to be completely eliminated for the drugs to be effective.

Unity Biotechnology was the leader of the pack with 2 of their drugs entering phase trials but failed the trial. However, the company seems to be working on other drugs. Numeric biotech is a company that develops senolytic drugs to selectively eliminate senescent cells to treat age-related diseases.

Rubedo Life Sciences develops drug molecules to target senescent cells using their discovery platform ALEMBIC and raised 12m $ in seed round in december 2020. Fox Bio is another developer of small molecules techniques intended to reduce senescent cells in human bodies. The company is a joint venture between Juvenescence Limited and Antoxerene, Inc., a portfolio company of Ichor Therapeutics, Inc.

The second approach is suppressing the SASP factor of senescent cells instead of eliminating them. Pathology of senescent cells (i.e the inflammation of healthy cells leading to accumulation of senescent cells) is driven by Senescence-Associated Secretory Phenotype, or SASP that causes chronic inflammation and inhibits stem cells. SASP also further contributes to aging by inhibiting DNA repair in non-senescent cells.

Since some senescent cells may still be useful in the body, this treatment could be relatively beneficial. Senolytic Therapeutics, Senisca, Atropos Therapeutics, Dorian Therapeutics, Oisin Biotechnologies are companies that have senomorphic drug pipelines.

Senostatic drugs is the third approach. Senescent cells develop protein molecules with age that prevent the immune system from clearing. Targeting these protein molecules and allowing the immune system to eliminate the senescent cells is the third approach. Senolytic Therapeutics has identified the protein molecule that hides senescent cells and has also developed treatments that eliminate this protein.

Here is a list with a quick tour of all companies working on senolytics.

2. NAD+

Another field of research that has been prominent in anti-aging research is NAD+. It is associated with multiple hallmarks of aging. They may underlie a wide-range of age-related diseases, such as metabolic disorders, cancer and neurodegenerative diseases. Evidence points to a strong relation between elevation of NAD+ levels and slowing or even reversing the aspects of aging as well as delaying the progression of age-related diseases. With aging, nicotinamide adenine dinucleotide (NAD+) levels in the cells decrease causing communication losses between nucleus and mitochondria. NAD+ is also important for energy metabolism, DNA repair, and epigenetic stability. Seragon Pharmaceuticals based in Tokyo recently announced the most advanced aging drug called Restorin that enhances NAD+ in cells.

3. Gene Therapy

A few companies are taking the approach of gene therapy to fight aging. Gene therapy constitutes:

a. replacing a gene that causes a medical problem with one that doesn’t

b. adding genes to help the body to fight or treat disease, or

c. turning off genes that are causing problems.

Libella Gene Therapeutics claimed in 2019 that it will administer volunteers(although it costs 1 million $ to ‘volunteer’) with a gene therapy that it claims can reverse aging by up to 20 years. Liz Parrish of BioVIva, became the first patient zero in 2016 to experiment with gene therapy that could intervene with human aging.

4. Cellular Reprogramming

An interesting thesis in the field of aging is that there are two different kinds of aging: the normal chronological aging and Epigenetic Aging, sometimes called Horvath clock, named after Steve Horvath. Epigenetic Aging is the study of processes that affect gene expressions without changing the DNA sequence. One such process is DNA Methylation. As we age, the methylation of DNA changes in a predictable way like a clockwork. The speed of this epigenetic clock is mostly dependent on genetics and to a lesser extent on lifestyle, and it is different for different individuals. A clinical trial led by Intervene Immune has given hopes that epigenetic aging could be reversed.

Cellular Reprogramming(remember epigenetic alterations?) has demonstrated that multiple aging hallmarks can be reversed. In his book Lifespan, Sinclair stated that he believes aging is the result of the so-called epigenetic changes scrambling how the body reads genetic code. A number of labs companies under David Sinclair and his team at Life Biosciences are working towards cellular reprogramming. Bitbio is a UK startup that is focused on cellular reprogramming. AgeX Therapeutics, Turn Biotechnologies, Reprocell are some of the companies working on this front.

Investment Landscape:

Led by David Sinclair, Life Biosciences and its portfolio companies are active developers of drugs designed to promote longevity and find treatments for age-related diseases. Metrobiotech is one of the portfolio companies with a drug development platform producing NAD+ enhancers to combat the adverse conditions of ageing. The drug is undergoing phase 2 clinical trials.

Jumpstart Fertility is another portfolio company tackling female reproductive decline with age. They are developing a drug that has the potential to restore fertility in older women or those who experience premature infertility. One of the leading companies in Life Biosciences’ portfolio working on the removal of senescent cells is Senolytx Therapeutics. Iduna Therapeutics is another portfolio company developing epigenetic reprogramming therapies that allow the rejuvenation and replacement of tissues that cannot regenerate themselves after injury or degeneration

Another parent company working focusing on rejuvenation biotechnology is Juvenescence. One of its portfolio companies, AgeX Therapeutics, is developing a platform that aims to unlock cellular immortality and regenerative capacity to reverse age-related changes in the body. The company is also in the phase 2 clinical trial stage. Insilico Medicine, Juvenescence AI, NetraPharma and LyGenesis are the other portfolio companies

There are a few interesting companies that are either privately held or have raised funds to push the frontiers of longevity. Elevian develops medicines that restore youthful regenerative capacity, with the potential to treat and prevent many age-related diseases.

Samumed, with 650 million $ in disclosed funding at a 12 billion $ valuation, is focused on developing therapies targeting a single, ageing-related signalling pathway that involves stem cell control, proliferation and self-renewal. Google-owned stealthy biotech Calico aims to discover and develop interventions that enable people to live longer and healthier lives.

As is the case with biotech companies, a lot of the rejuvenation biotech companies have already gone public. Unity Biotechnologies is a public company developing therapeutics that selectively eliminate or modulate senescent cells through localized therapies. Proteostasis/Yumanity Therapeutics, Cohbar, Lineage Cell Therapeutics, Geron and RestorBio are among other publicly listed companies that fight aging.

On the venture capital front, there are multiple funds that are specifically focused on longevity such as Methuselah Fund, Longevity Fund, Apollo Health Ventures, Longevity Capital, Rejuveron, Longe Vc, Longevity Vision Fund. For accredited investors, Sp8ce VC is a rolling fund that focuses on longevity and space tech.

Recommendations:

Lifespan: Why we age and why won’t have to by David Sinclair is perhaps the best book out there on aging. It covers an interdisciplinary approach to understand why aging needs to be treated as a disease, what is the current state of anti-aging research, the moral as well as philosophical discussions around longevity and challenges as well as concerns surrounding the field.

Fight Aging, Lifespan, and Sens Research Foundation provide great resources and news on up-to-date research taking place in the field of anti-aging.

Laura Deming has drafted a great beginner’s guide to understanding longevity and how we might increase healthy lifespans.

For a deep dive into longevity, Nintil’s work is unparallel.

Perhaps, it is time to debate more about the implications of anti-aging and start planning for life at the age of 150, 300 or even 1000?

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