Epigenetic Basis of Cellular Senescence- An Insight into Immortality

We've all watched movies that harbor immortal characters. 'The Age of Adaline' is one such movie in which the protagonist, Adaline Bowman, becomes immune to the ravages of time, meaning she never ages another day! The movie elucidates the process of "Von Lehman's principle of electron compression in deoxyribonucleic acid", by which, in the movie, aging supposedly halts. Otherwise, electron compression is a hoax.

Everyone wants to live a long life, but what do you feel about the future prospects of aging research? Do you feel that scientists will-

1. Increase the human 'healthspan' (the part of our lives during which we are in good health)

2. Create a computer chip that will store human consciousness and memory

3. Develop a 'safe' method of cryogenic electrocution which will reverse the deterioration of telomeres responsible for aging?

For all of you who have chosen options 2 and 3, don't feel disheartened. In the near future, research on aging will be primarily based on increasing the human 'healthspan' so that majority of the people live longer lives in good health without diseases such as Alzhiemer's, coronary artery disease (CAD), etc. Options 2 and 3 can only be made possible when scientists understand the proper mechanism of cell senescence with respect to epigentics.

Epigenetics is the study of heritable phenotype (expressed genes) changes that do not evolve from alterations in the DNA sequence. For instance, twins turn out to be very different as they age mainly because of differences in environmental/external factors such as diet, exercise, social relations, etc. and not necessarily due to their genetic material, as it is exactly the same.

The video above accentuates three examples of discoveries vis-à-vis human longevity and aging: Senescent cells, NAD+ and Stem Cells. However, it does not make connections between Aging and Epigenetics, which is the predominant scope of this blog post.

"Genetics loads the gun, and the environment pulls the trigger"- Dr. Sara Gottfried

Interesting fact: Many scientists consider 'moon jellyfish', Aurelia aurita, as immortal because they show no evidence of senescence (biological aging). So, is studying 'moon jellyfish' the key to slowing aging and extending our lifespan (or healthspan)?

Before we talk about extending our lifespan, we must answer the following question.

Why do we age?

The following picture shows the 'hallmarks' of aging.

Cellular senescence: After every cellular division, cells lose DNA at the ends of their chromosomes known as telomeres. The deterioration of these telomeres is what drives a cell towards senescence. Studies have found links between the accumulation of these zombie-like cells—senescent cells— with cardiovascular disease, diabetes, etc.

Stem Cell exhaustion: Stem cells are cells that are known for their potential to differentiate into specialised cell lineages. A child's embryo contains pluripotent stem cells which give rise to the wide range of special cell types ranging from neurons to epithelial cells to cardiac muscle cells. The exhaustion of stem cells (especially adult stem cells such as hematopoietic stem cells that give rise to blood cells) can inevitably cause aging.

Telomere Attrition: The deterioration of telomeres at the ends of our chromosomes halts cell division and causes the accumulation of senescent cells. As the number of senescent cells in the body increase, so do the chances of deadly diseases.

Altered Intercellular Communication: It refers to changes in endocrine, neuroendocrine and neural pathways which can lead to mechanisms of aging. Poor intercellular communication is related to many diseases such as atherosclerosis and arthritis which increase exponentially with age.

Deregulated Nutrient-Sensing: Metabolism and its byproducts, over time, damage cells via oxidative stress, endoplasmic reticulum stress, calcium signaling, and mitochondrial dysfunction. Once nutrient sensing pathways are damaged, a misguided hypothalamus will signal for greater food intake, even when the body doesn't require it. Age-related obesity, diabetes and other metabolic syndromes result.

Genomic Instability: This refers to a high frequency of mutations within the genome (an organism's entire DNA sequence) of a cellular lineage/type. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy (abnormal number of chromosomes within a cell) which may affect the polypeptide or protein that is coded for by the gene.

Loss of Proteostasis: Chaperones are a group of proteins that have functional similarity and assist in protein folding. A loss of chaperones can occur due to a failure to transcribe the correct DNA, and, sometimes, the chaperones get stuck in protein aggregations and cannot move. This trapping of chaperones is linked to Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS).

Epigenetic Alterations:

Harvard Professor, David Sinclair, hypothesises that aging is caused by the loss of information in our 'epigenome' instead of the heritable genetic material in our chromosomes. The 'epigenome' is a collection of chemical tags that serve as chemical modifications to DNA and histone proteins, and help regulate the expression of genes within our genome. Professor Sinclair believes that alterations in these epigenetic chemical tags may cause aging because changes in the epigenome will directly affect gene expression and synthesis of proteins in our bodies. Reading methylation patterns (methyl groups act as chemical tags and are part of our epigenome) can help scientists determine an individual's current age and the approximate age at which one is going to die!

If Professor Sinclair's hypothesis is correct, and if epigenetic alterations really cause aging, we can take steps right now to increase our lifespan.

There are certain 'longevity genes' in our chromosomes that prevent us from aging by reversing cellular degeneration, averting protein misfolding and regenerating the deteriorated telomeres at the ends of chromosomes. However, these 'longevity' genes are expressed lesser and lesser as we grow older due to changes in epigenetic information, meaning we age irreversibly.

There are 5 ways by which we can slow our aging:

1. Avoid DNA damage- Avoid X-rays, and UV rays coming from the sun

2. Eat less- Caloric restriction

3. Eat less protein (amino acids)

4. High intensity interval training- Intense exercise to increase heart rate

5. Be uncomfortably cold or uncomfortably hot

These things will better express your body's 'longevity' genes by maintaining your epigenome. Personally, I would wait for further research to be done on aging rather than trying these ways to slow aging. But slowing aging isn't enough, right? What about reversing aging? Well, in 2012, a scientist named Shinya Yamanaka received the Nobel Prize for discovering four factors, which when applied to an adult cell in gene therapy, would reset the whole epigenome back to how it was when the cell was an embryo. The Reverse Aging Process is a topic for another post!

"Food is medicine. We can actually change our gene expressions with the foods we eat"- David Perlmutter.

References:

-“LEAF: Life Extension Advocacy Foundation.”Lifespanio, www.lifespan.io/.

-How to Slow Aging (and even reverse it) | Veritasium -Youtube. https://www.youtube.com/watch?v=QRt7LjqJ45k

-How to Cure Aging – During Your Lifetime? | Kurzgesagt – In a Nutshell- Youtube. https://www.youtube.com/watch?v=MjdpR-TY6QU.

-PMC, Europe. Europe PMC, europepmc.org/article/PMC/3836174.

-Sharma, Yashaswi. “Stem Cells- Sources, Characteristics, Types, Uses: Developmental Biology.” Online Microbiology Notes, 4 Jan. 2020, microbenotes.com/stem-cells/.

-“Telomere Shortening, Conceptual Illustration - Stock Image - F020/1445.” Science Photo Library, www.sciencephoto.com/media/887538/view.

-Jse. “Hallmarks of Aging Role of Glycation Part 6: Deregulated Nutrient Sensing.” Personal Trainer Certification, Nutrition Courses, Fitness Education, 9 Mar. 2018, www.nestacertified.com/hallmarks-of-aging-role-of-glycation-part-6-deregulated-nutrient-sensing/.

-“Understanding Genetic Mutations: Why Do Some Cause Disease, While Others Don't?” Genetic Literacy Project, 2 Apr. 2018, geneticliteracyproject.org/2018/04/02/understanding-genetic-mutations-why-do-some-cause-disease-while-others-dont/.