Cornering Aging: the various forefronts of longevity research.

K
8 min readJun 1, 2022

To know the lay of the land in longevity research, it’s important to understand why we age. It’s clear that aging is a multivariable problem but do we know what the variables are? And can we address them?

Well yes, and kind of. There are basically nine fundamentals ‘agers,’ also called the hallmarks of aging. And there are therapeutic techniques that attempt to address specific hallmarks, some more successful than others.

So without further adieu, let's deep dive into the nine hallmarks of aging, therapeutic tactics to tackle them, and a few key organizations using these approaches!

The Hallmarks of Aging.

The nine fundamental hallmarks of aging are:

  1. Telomere Erosion.
  2. Genetic Damage.
  3. Epigenetic Alterations.
  4. Cellular Senescence.
  5. Stem Cell Exhaustion.
  6. Loss of Proteostasis
  7. Deregulated Nutrient Sensitivity.
  8. Mitochondrial Dysfunction.
  9. Altered Intracellular Communication (1).

For the purpose of this article, we’re going to focus on the first five.

Telomere Erosion

Background.
Telomeres are meaningless repeats of the nucleotide sequence “TTAGGG” at both ends of a chromosome. They’re replicated by the DNA polymerase enzyme, Telomerase.

Telomeres are an effective first line of defence against chromosome damage during cell replication. Each cell division chips away at these telomeres, eventually deteriorating them completely. This would typically expose a cell to genetic damage; however, when telomeres are critically short, it triggers a DNA damage response (DDR) in the cell, sending it into senescence. This eventually kills the cell (2).

Therapies.
There are a number of gene therapies that focus on expressing more of the telomerase enzyme. Maintaining telomere length during cell replication is key to protecting a cell from entering senescence, and undergoing apoptosis prematurely. Unfortunately, over-expression or reactivation of telomerase also stabilizes cancer cell telomeres, allowing them to proliferate ‘endlessly.’

Telomerase up-regulation also significantly delays traditional replicative senescence provoked by shortened telomeres. In order to enter senescence, the cell has to trigger a DDR through other means, such as oxidative stress.

Over this elongated existence, the cell is left with significantly more genetic mutations from DNA damage. Thus, when the cell enters senescence, it is far more likely that tumor-suppressing genes, such as the p53 gene, have been deactivated. This enables the cell to bypass senescence and enter an immortal cancerous state. Through replicative senescence, the probability of producing a cancer cell is 1 in 100,000 -10,000,000 cells. Telomerase over-expression increases that probability to one in every cell (3).

Fortunately, there are telomerase gene therapies in development that do not promote cancer, using recombinant viral vector administration!

A 2012 study identified that adeno-associated viral (AAVs) vectors were able to lengthen mice's lifespans between 13 - 24%. The therapy had positive effects on several biomarkers of biological age and also decreased the risk of osteoporosis, and several metabolic disorders. Treated mice did not experience higher occurrences of cancer than their control counterparts. (4)

Most companies developing longevity telomerase therapies are still demonstrating efficacy in human clinical trials.

Genetic Damage

Background.
Every day, cells experience 10,000 natural occurrences of DNA damage. This damage arises from unwanted oxidation. ROSs, free radical byproducts of metabolic reactions, oxidize cellular DNA. This changes the structure and compromises the nucleotides’ function.

External factors such as UV and pollutant exposure can contribute to the frequency of DNA damage. Most of this damage is repaired in the body by removing the damaged nucleotide and synthesizing a new one in its place. However, as we age, certain reparation pathways get less and less effective.

For instance, menopause occurs when women experience a decline in ovarian reserve. A 2020 paper in the Human Reproduction Update Journal, suggested a correlation between the decline of double-stranded breaks (DSBs) repair mechanisms and the onset of menopause. The homologous recombination (HR) mechanism, uses BRCA1, ATM, MRE11, and Rad51 genes to repair DNA.

When DSBs accumulate in immature oocytes or ovarian cells, the HR mechanism is usually able to repair the damage. Unfortunately, these genes experience age-related decline, allowing the DSBs to accumulate and render the cell dysfunctional. Thus, the decline in ovarian reserve (5).

Therapies.
There is some promising research that stimulates the DDR using its activators, like chloroquine. The HR mechanism genes and stimulated DDR were able to work in tandem to successfully extend the lifespan in worms and mice (6).

This hallmark is also well addressed through preventative measures. Industry experts often recommend ingesting antioxidants to neutralize ROSs and wearing sunscreen to avoid radiation damage!

Epigenetic Alterations

Background.
The epigenome is essentially another layer on the genome, regulating gene expression. It’s quite crucial to cell differentiation, with an epigenetic pattern establishing the difference between a skin cell and an aortic cell.

Histones are basic proteins that DNA is wound around. Methyl groups are added to these histones to modify the activity of a gene without interfering with the sequence itself. These post-translational edits are usually made with the assistance of epigenetic enzymes.

Most of the age-related modifications in gene expression are due to epigenetic alterations. When DNA gets damaged, it is (usually) routinely repaired. The reparation process can often prompt changes in histone methylation, altering epigenetic expression.

If this were to happen to an immune cell, a change in gene expression could suppress crucial support genes, turning the cell dormant, and leaving the body vulnerable to disease. Epigenetic alterations are responsible for a number of genetic imbalances and disruptions that occur with old age.

Sirtuins are a family of signaling proteins responsible for cellular response to oxidative stress. SIRT1, SIRT2, SIRT6, and SIRT7 can modify histones and influence epigenetic enzymes; they are crucial to maintaining epigenetic expression (7).

Sirtuin activity is regulated by the coenzyme nicotinamide adenine dinucleotide (NAD+). NAD+ is the active, or oxidized counterpart of NADH; a higher NAD+ to NADH ratio leads to higher sirtuin levels and subsequently, slowed aging (8).

Therapies

One of the primary recommendations to prevent epigenetic alteration is certain lifestyle changes. Factors such as diet, physical activity, substance abuse, pollution, and stress can affect your DNA methylation profile and biological age. Unique practices such as enduring extreme hot or cold temperatures, or intermittent fasting can actually stimulate NAD+ levels in the body.

There are a number of supplements that focus on increasing NAD+ levels, to up-regulate sirtuin activity in the body. Nucleotides such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are observed as precursors to NAD+ and also have supplements.

Companies such as Elysium Health develop supplements that increase NAD+ levels to prevent metabolic aging and epigenetic alteration.

Cellular Senescence

Background
There are three main varieties of cellular senescence:

  1. Replicative senescence — when a cell has hit its maximum number of cell divisions, and is naturally stopped from replicating.
  2. Oncogene-induced senescence — when oncogenes, genes responsible for cell replication, are over-expressed, triggering excessive cell proliferation. In order to prevent a tumor, the cell activates two tumor suppressant pathways. These stimulate cellular senescence.
  3. Stress-induced senescence — when oxidative stress causes single and double-stranded breaks in DNA it activates a DDR. This triggers a signaling pathway, prematurely sending a cell into senescence (9).

The purpose of cellular senescence is to stop replication and trigger apoptosis, and cell suicide. Some cells are able to resist apoptosis by activating ‘survival’ pathways and inhibiting apoptosis pathways.

When the cells fail to conduct apoptosis, it tries to alert the immune system by secreting inflammatory factors and employing cellular signaling. Ideally, the immune system would send inflammatory cells to the area to clear out the senescent cells.

As the immune system weakens with age, these two systems backfire. The inflammatory factors cause chronic inflammation and the cellular signaling encourages senescence in surrounding cells, especially stem cells (9).

Therapies
There is a stream of small molecules that induce apoptosis in senescent cells, called senolytics. Senolytics stimulate apoptosis pathways and inhibit ‘survival’ pathways.

The existing generation of senolytics targets specific age-related diseases that are resultant of cellular senescence. For instance, senescence-induced inflammation can severely compromise joint integrity. Thus, Unity Biotechnology is currently using analytics to treat osteoarthritis (10).

Companies such as OneSkin and resTORbio focus on the topical application of senotherapeutic molecules. A lot of senescent cells accumulate in the skin, due to DSBs from UV radiation. Topically applied senotherapeutic peptides or molecules can induce apoptosis and reduce senescent burden in the skin.

Stem Cell Exhaustion

Background
When senescent cells signal to nearby cells, they also peer pressure them towards senescence. Stem cells are quite impressionable, and therefore, easily join the senescent ranks. Over time, the reserves of stem cells deplete; this is detrimental to regeneration and cell turnover rate.

Additionally, as stem cells age, the compilation of genetic damage, epigenetic alteration, and cellular senescence impedes their function. The stem cell’s ability to differentiate and its regenerative capabilities are affected.

This can lead to a host of age-related pathologies including cancer, heart disease, cognitive decline, type II diabetes, and osteoporosis.

Therapies
Currently, the only established stem cell therapy is an immature blood cell or hematopoietic stem cell transplantation. Both malignant and non-malignant diseases can be treated with this stem cell infusion. It is used to induce blood cell production in individuals with weakened immune systems.

A method in development called, reprogramming could be used to replenish stem cells. In 2006, the Yamanaki factors (Oct4, Sox2, Klf4, C-Myc) were used to dedifferentiate an adult cell into a stem cell. These cells are referred to as iPSCs, induced pluripotent stem cells.

Reprogramming not only dedifferentiates cells, but it also has to rejuvenate properties. AgeX Therapeutics is harnessing this reprogramming to create long-lasting cells to tackle degenerative diseases. Unfortunately, there is a cancer risk associated with dedifferentiation (11).

Gameto Gen is experimenting with cellular reprogramming to tackle ovarian aging. The dedifferentiated iPSCs are differentiated into granulosa-like cells, cells within ovaries. The replenishment of these cells assists with successful egg maturation. This strategy can be used to increase egg production in women experiencing infertility, and can eventually be used to postpone or eliminate menopause (11).

Partial reprogramming is another strategy that attempts to achieve rejuvenation without dedifferentiation to eliminate the cancer risk. It doesn’t necessarily replenish stem cells but it takes advantage of the Yamanaki factors to encourage rejuvenation.

The perfect amount of the Yamanaki factors has to be delivered using viral vectors to induce rejuvenation but prevent dedifferentiation. Altos Labs will mainly be using this approach, referring to it as rejuvenation programming.

Takeaways

  • There are nine fundamental hallmarks of aging. Most therapeutic approaches tackle telomere erosion, genetic damage, epigenetic alteration, cellular senescence, and stem cell exhaustion.
  • There are telomerase gene therapies in development that do not promote cancer, using recombinant viral vector administration. These were able to increase mice's lifespan between 13–24%.
  • Stimulating DNA Damage Response (DDR) activators, to prevent genetic damage, and increased mice and worm lifespan.
  • SIRT1, SIRT2, SIRT6, and SIRT7 are crucial to maintaining epigenetic expression and are dependent on NAD+/NADH ratios. Higher NAD+/NADH ratios mean higher sirtuin levels and subsequently, slowed aging.
  • Senolytics are small molecules that stimulate apoptosis pathways and inhibit ‘survival’ pathways to prevent cellular senescence.
  • Partial reprogramming is a strategy that rejuvenation cells without dedifferentiating them into iPSCs, induced pluripotent stem cells, to eliminate the cancer risk.

References

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/
  2. https://journals.physiology.org/doi/full/10.1152/physrev.00026.2007
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915101/
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494070/
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935693/
  6. https://www.nature.com/articles/s41684-018-0105-9
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610301/
  8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514220/
  9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214092/
  10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816502/
  11. https://pubmed.ncbi.nlm.nih.gov/31475896/

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K

UC San Diego Biotech Engineering | Reproductive Longevity Enthusiast