Is Genetic Reprogramming the answer to age reversal?

reverse-ageing

Is Genetic Reprogramming the answer to age reversal?

Humankind’s eternal quest is at the threshold of an exciting breakthrough that makes age reversal a reality rather than a pipe dream

Imagine the evil stepmother in a modern retelling of Snow White and the Seven Dwarfs. Would her mirror dare to mock her ageing face? Indeed not, especially when science is racing towards the next frontier of humanity’s accomplishments: age reversal, helping us move away from snake oil marketing for anti-ageing.

The inevitability of ageing is as natural as the psychological obsession with youth. Humanity has forever wanted to remain young and invented whatever it takes to fight ageing – pills, potions, elixirs, creams, and serums that seduce and betray. Yet our faith in their magical promises continues. But now, finally, we are moving beyond pills and potions as we enter the era of Genetic Reprogramming. It brings a new hope: that ageing is inevitable but not irrevocable.

What does it mean? It means that we can decelerate the pace of ageing and enjoy a state of sustained freshness in our bodies for a longer time.

Let us examine how it works.

The building blocks of life

The life of an organism is a three-stage process of birth, growth, and death. It is an encoding program in every cell of the organism, which, as it ages, sees its cellular state undergo attrition to the point when the organism ceases to exist, leading to death.

The march of the birth-to-death process leads to ageing, an observable physical phenomenon accompanied by a decline in mental and psychological faculties due to cellular deterioration. The cell is timed for eventual demise due to its protein degeneration. Since the energy of all living beings is a structural and functional expression of proteins, any change in them will affect cell functionality.

Enter DNA, the building block of life. Remember the expression, ‘It’s in your DNA?’ There is a reason why it has a deep meaning.

DNA or deoxyribonucleic acid is a long molecule that contains every being’s unique genetic code and is present in nearly every cell of all living things. Most of the DNA is situated in the cell nucleus. An essential function of DNA is to replicate or make copies of itself when cells divide, so each new cell has its exact copy in the new partition.

The master key to the process of birth and ageing lies in the DNA’s protein sequences encoded in it. When there is a DNA alteration (natural or induced), it will reflect in the protein outcome and eventually impact it.

The DNA found in the cell’s nucleus is termed nuclear DNA, and the complete set of nuclear DNA in an organism is its genome.

So, having got a basic idea of the role of DNA in our bodies, let’s understand how any alterations in the cause ageing.

Factors that contribute to DNA alterations

Is DNA susceptible to changes with time? Yes. What are the reasons that lead to this change?

It’s because of the chromosomes inside the DNA.

What are chromosomes? These are structures inside cells that contain the organism’s genes. And genes are segments of DNA that include the code for a specific protein that has a role to play in different types of cells in the body. 

Every chromosome in our genes has a compound structure at its ends called telomeres. It’s like having a microscopic cap at the chromosome’s both ends as a protective measure. They help the chromosome replicate itself during cell division, and every time a cell carries out DNA replication, a chromosome gets shortened. The only part of the chromosome impacted is the telomere, which loses a microscopic fraction in this process. This cycle of DNA replication eventually shaves off a telomere’s length, and it gets shorter and shorter till it cannot support a chromosome’s length. At this stage, with the chromosomes facing a challenge, the cell cannot survive and dies. The more the cell death due to challenged chromosomes, the more significant the impact on the organism and the faster its decline.

In cancer patients, for example, high doses of radiation and chemotherapy can lead to DNA alteration at an accelerated pace leading to ageing.

Disease, deterioration, ageing and eventually death result from a genome under pressure.

How does DNA alteration contribute to ageing and cell cycle arrest?

As the genome gets more unstable due to telomere shortening, to halt faulty transfer to daughter cells, nature sets into motion steps that try to conserve the stability of the genome. After all, evolution is all about the survival of the fittest. The natural selection comes into play in two ways for a true-blue transfer of genes to the next generations. The replication of the DNA (called replicative senescence) is stopped, or Apoptosis (cellular death) is triggered by promoting the DNA damage pathway.

Cell cycle arrest is the immediate consequence of DNA alteration.

Cellular housekeeping: The body is a taskmaster

Once the cell cycle arrest kicks in, what follows is a self-destruction of the cell or autophagy as it is called in scientific terms.

Autophagy is the body’s automated waste disposal process to remove junk and clean up the internal environment. Elimination of the dysfunctional cells and their accumulated protein and lipid content and other stuff makes room for new cells. Autophagy is mainly responsible for longevity and slowing the ageing process.

What if cellular housekeeping fails?

If the cells do not undergo cellular death naturally, the redundant, aged, and misfit cells survive as ‘senescent’ cells. The extent and duration of DNA damage govern Apoptosis (cellular death) or senescence (senile cells). Prominent and short-term DNA damage chooses Apoptosis, whereas mild and long-term injury takes the senescence route.

How do senescent cells impact ageing?

They secrete senescence-associated proteins (SASP) such as cytokines, chemokines, growth modulators, active lipids, metalloproteases, angiogenic factors, and pro-inflammatory cytokines. All these contribute to cell ageing.  

Senescence cells can affect the surrounding cells and communicate with them, inducing senescence in other cells. The overcrowding of senescent cells and pro-inflammatory protein secretion lead to a sharp reduction in stem cells. It leads to tissue impairment, loss of immunity, cardiovascular diseases, osteoarthritis, sarcopenia, and neurodegenerative conditions.

For example, in cardiovascular diseases, damage to collagen of the blood vessels makes them stiff, giving rise to hypertension. The thickening of the vessel walls due to reactive tissue formation results in atherosclerosis, and the deterioration in cardiac muscle cells contributes to cardiac myopathy.  

One of the reasons for myocardial infarction in older individuals is cardiomyocyte (cardiac muscle cells) atrophy caused by senescent cells. 

Neurodegenerative diseases like Parkinson’s and Alzheimer’s also reveal markers of senescence cells.

The double role of senescence cells in cancer

There is evidence of both types of senescence responses in cancer – friendly and unfriendly.

Friendly action: We know that tumour formation is caused due to unstoppable cell division.

Due to their non-proliferative nature, senescent cells do not initiate tumorigenesis (or the formation of tumours). Logically, as the tumour suppressor genes are most functional in senescence, they inhibit the vital enzymes responsible for cell division to stop proliferation and, as a result, tumorigenesis.

Unfriendly action: There is evidence of senescence cells providing a supportive environment for cancer cells through their secretions and mediating the movement of certain types of cancer cells to induce a version of metastasis. Therefore, senolytic drugs or drugs that clear senescent cells are used to arrest tumour progression.

Any damage or alteration in DNA originating from senescence can disturb the tumour suppressor genes and activate tumorigenesis.

Are anti-ageing and reverse ageing compatible?

We all strive towards betterment, however challenging it may be. Even during a terminal illness, the hope of halting the ageing process remains robust in the patient.

Anti-ageing processes restrict cell deterioration; however, they cannot restore senescent cells to health.

However, some methods promote a healthy, age-reversing lifestyle:

  • Senolytic drugs can induce Apoptosis and remove senescent cells from the tissues.
  • Dietary restrictions such as Intermittent Fasting and a ketogenic diet can detect nutrient-sensing pathways to hold back the ageing of healthy cells.
  • The drug Rapamycin mimics the effects of calorie restriction and promotes autophagy.
  • Inclusion of antioxidants in the diet can save damage from ROS or Reactive Oxygen Species. ROS are byproducts of cellular metabolism that act as secondary influencers on the body’s physiological functions. There is rising evidence of ROS contributing to pathological conditions.

Reverse ageing replaces degenerated cells with stem cells, which have the potential to multiply and differentiate into various types of cells as per the body’s needs. Therefore, a reserve of stem cells is a backup to the body’s ongoing processes.

Reverse ageing is an innovative way to reset the cells’ biological age to zero by transforming senescent cells to their embryonic state called pluripotent cells or stem cells with which we started our life. It is paving the way for reversing irreparable organ damage.

It is a promising therapeutic mechanism for diseases like glaucoma, neurogenesis, type 2 diabetes, cancer, cataract, myocardial infarction, etc. It can rejuvenate the skin and muscle cells to help them renew their youthfulness.

The idea of cellular rejuvenation emerged from detecting epigenetic biomarkers in senescent cells. Biomarkers are biochemical substances in the body that indicate a pathological condition; they are calculated by observing metabolic activities under duress. The number of biomarkers can determine the cell’s epigenetic age, which differs from the organism’s chronological age. 

Some important epigenetic biomarkers are: 

  • DNA’s loss of strength: As the telomere shortens and the DNA gets more methyl molecules, it indicates lesser gene activity and is termed a biomarker.
  • Cellular decline: A loss in the integrity of the cell’s nuclear membrane and the inner mitochondrial membrane hinders the movement of selective molecules and ions. 
  • Energy loss: The presence of SA beta-galactosidase molecules, which play a vital role in producing energy and carbon generation through breaking down lactose,  and interleukin molecules which modulates the immune system etc., are also epigenetic biomarkers.

These biomarkers are the byproducts of metabolic activities over a period of time which indicates the need for genetic reprogramming for the rejuvenation of the aged cells. 

What is Genetic Reprogramming (GR)?

To understand GR, we must first know the lifecycle of a cell. The embryonic cells or pluripotent cells divide and differentiate into various types as per their genetic role. Once they differentiate and mature, they take up their specific function: e.g., nerve cells work for the nerves and muscle cells for the muscles. 

If the cells are in a pluripotent state, they can divide and nourish. So, if aged or senescent cells are rejuvenated to pluripotent status, they can replenish the loss of aged cells and generate healthy young cells to start their functions afresh.

Japanese life scientist Shinya Yamanaka (2006) activated four genes in human skin cells and transformed them into pluripotent cells, which started yielding collagen again to heal wounds.

However, one big question remains. What if the cells lose their identity due to the unification into pluripotency? How will they differentiate to perform their respective functions?

This aspect is essential to probe because repeated activation of Yamanaka factors can give rise to teratomas (tumours made of confusing cell mass).

Carrying forward this research, the Babraham Institute in the UK restored the identity and proper functioning of the cells, which proved to be effective in curing Alzheimer’s and the MAF gene (protein-coding gene) to cure cataracts.

The demerits of the pluripotent program in vivo lie in the loss of cellular identity and the ability of cells to self-renew, causing a high risk of cancer. The only way to eliminate this problem is to boost cell plasticity (the cell’s ability to change its identity or role). In other words, research has found that specific matured cells can de-differentiate under certain conditions and perform for the body’s optimal health. Promoting this ability through pluripotency can transform the role of cells in renewing the body’s anti-ageing ability.

Goals of Genetic Reprogramming:

  • Choosing factors related to diseases and ageing based on DNA methylation and halting their progress.
  • Analyzing age-associated genes and related outcomes.
  • The enhancement of cellular health to halt ageing.

Conclusion

Humankind’s eternal endeavour to rewind the biological clock affirms the fundamental truth that our existence is merely a play of genes. We are a collection of cellular functions masterminded by genes, and the ageing game is just a toss of the gene coin.

So, if we can control the state of play at the molecular level, we can keep the foundation strong. This breakthrough is now at an exciting stage to be applied to the human body.

We are at the threshold of what we have been dreaming all along: realizing the promise of non-fading youth.

Ayana Dasgupta Kundu

Ayana Dasgupta Kundu

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