Are We Capable of Curing Ageing?

Can ageing be cured? Before I discuss whether we can cure ageing or not, let’s discuss what is ageing and why do we need to cure it in the first place? I know what most of you might be thinking, how can one possibly cure ageing? It’s not a disease, right? It’s a natural phenomenon that is inevitable. If you are feeling the same, please wait a minute, and I’ll answer all the questions.

Cholera was also a part of life unless we started separating sewer water from drinking water. Being natural doesn’t make anything reasonable or necessary.

It was natural to die at the age of 50 a century ago, but our average life expectancy increased significantly after the industrial era. But still, the maximum life expectancy of a person remained the same; it’s like a hard breaking point. Even though we are living a healthier and longer life than ever, it seems crossing the 80 years mark is an achievement, and crossing the mark of 100 years is a miracle in itself. These numbers didn’t change throughout history. Even though the number of people crossing these ages has increased, the average maximum life span is less than 100. The oldest human ever lived was a woman named Jeanne Calment, 122 years, 164 days. It won’t be wrong to say women live longer than men, as all the top centenarians on the list are women.

What is Ageing?

Ageing is more of a physical phenomenon than a biological one; human ageing is not much different than that of a car, as a car or any other animate object wears and tears due to its day to day everyday uses so as our bodies. Our bodies and their cells do a lot of complicated work to maintain this complex system, be it metabolism or respiration, every single process that our body does at the cellular or organism levels. A small amount of damage happens with each process, and these accumulated damages take the form of a fragile and aged body with time. 

Along with these, there are some genetic factors too; as a species, we are supposed to live just enough that we could produce offspring and let them live freely, living long may interfere with the newer generation, which isn’t favourable from a species point of view. But some species don’t follow these rules and live long enough to disprove this theory. Leonard Hayflick, a professor of Anatomy at UCSF School of medicine, theorized that a cell could divide only a fixed amount of numbers; for example, a human cell divides only approximately 50 times before it dies. Now we know the reason behind it is that telomeres (small noncoding stretches of DNA at the end of chromosomes that protect the coding genes) get shortened every time a cell replicates. After a certain number, the DNA gets so damaged that the cell dies. 

Till now, you have known ageing isn’t a simple process, and there’s no one cure for all approach that can be applied here; here is a simple diagram of human metabolism ( you aren’t supposed to read all that), and yes, it’s simple, and I’m not any sarcastic. It’s the known* pathway of a small part (metabolism), among other things.

If you can’t measure it, you can’t improve it.

-William Thomson (Iris physicist)

 

It’s tough to understand ageing and why it happens; still, scientists have classified ageing pathways in the following parts for simplicity.

Hallmarks of Ageing

1. Genomic instability

As we get old many damages occur to our genomic material due to the normal functioning of the body. these damages then accumulate with age and cause many problems as defective DNA can’t produce protein and hence isn’t good for the body.

2.Telomere Attrition

Telomere is located at the end of our chromosome, and protect our DNA from wear and tear just like an aiglet (the plastic tip of a shoelace) saves wear and tear of shoelaces. But with age, our telomeres get shorter and shorter with every dividing cell, and after a certain number of cell division (Hayflick Limit), cells die due to fatal damages.

3.Epigenetic alteration

Epigenetic ( Epi-over or in addition to genetics) is a modification of our genome without changing its coding at the base-pair level. It changes gene expression in the cells and happens due to external factors like the environment or our lifestyle.

For an analogy, let’s say your house is your genome, and the rooms are your genes. If you have to make any room inaccessible to anyone, you can either destroy it (genetic changes) or put a lock on the door (epigenetic modification). Epigenetic modifications affect the ageing process to a large extent. Methylation and histone modifications are some of the main types of epigenetic modifications that occur with age. Methylation blocks many gene transcriptions (from gene to RNA, thus blocking normal protein synthesis) essential for healthy ageing. In one case where a lady truck driver drove a truck for 28 years, her right face faced more sunlight than the left side throughout those years, resulting in more wrinkles on the right.

4.Loss of Proteostasis

As you know, proteins are the key ingredient for any organism. Proteins are long polymer of amino acids which need to be folded in a certain way to function properly. Chaperons are the enzymes that help them fold properly, and the proteins that don’t get folded by chaperons are degraded by the autophagy-lysosomal system and ubiquitin-proteosome system ( in simple words, these are kind of Police just bashing bad guys, i.e. misfolded proteins). But with age, these regulatory systems don’t work correctly, and the accumulation of misfolded proteins due to lack of autophagy causes many old age diseases like Alzheimer’s and Parkinson’s.

5.Deregulated nutrient sensing

As we know everything we consume is converted into ATP at the end, but as we grow old, our body’s ability to convert nutrients and break it down into the smallest energy currency aka ATP decreases.

6.Mitochondrial dysfunction

Due to the normal energy-generating process, our mitochondria accumulate a lot of damage as we grow old and become unreliable. These damages can harm us in various ways. Two of the most important harms are

  • More ROS generation- ROS or reactive oxygen species are a king of free radical, which can damage cellular component, leads to inflammation and sometimes cell deaths.
  • Less NAD+ generation- NAD is a precursor of many metabolic pathways, and lower levels of NAD leads to lower energy production.

7.Cellular senescence

After a certain number of cells division, cells stop dividing and reach a senescent stage when they can’t divide further. This mechanism prevents cells from becoming cancerous, but at the same time, these senescent cells get accumulated with age. You can say these cells Zombie cells because, like zombies, they are theoretically dead but still wander freely and secrete toxic elements like ROS and other interleukins, which is harmful to normal cells. This secretome property is also known as SASP ( senescence-associated secretory phenotype). These senescent cells are found in large numbers in the tissues of older individuals suffering from chronic disease.

8.Stem cell exhaustion

Stem cells have the capabilities to divide and take the form of any cells. When we got injured, stem cells help us to recover from those injuries. At young ages, we have a lot of these stem cells, and that’s why we recover soon. But as we grow older, we exhaust our stem cells leading to many old age problems like sarcopenia (muscle loss happens due to loss of muscle stem cells or satellite stem cells), osteoporosis (decaying Bone).

Can We stop ageing?

Before you dive deep, you have to believe ageing is a problem. Also, some diseases never occur in your 20s to 40s but happen to everyone in one’s 50s or older. There must be a core underlying problem for all of the diseases. We have labelled some diseases as diseases of old age like Alzheimer’s and Parkinson’s, and some we labelled as old age symptoms like sarcopenia.

“The First step in solving a problem is to recognize that it does exist.”

– Zig Ziglar

So If it’s so important, then why nobody has thought about it? Has anyone tried to solve it before, or are we the first generation to tackle this problem? Hold on. I am going to answer all of that. First of all, it’s not that curing ageing is any new concept. Curing ageing and achieving immortality is found amongst many of the most ancient stories. The only difference is now we are more equipped and taking this problem more scientifically rather than doing some witchcraft already done in the past. Even in 259 BC first Chinese emperor, Quin Shi Huangdi, buried his 8000 terracotta warriors under the ground, hoping that he’ll be alive once again with his enormous army. He used to take mercury as a cure for ageing, but ironically he died of mercury poisoning. History has many examples like this one, but none of them used scientific approaches as we are using today.

Modern Approaches to curing ageing

The Basic Philosophy of modern anti-ageing research is quite simple, learn from long-lived species and apply that knowledge to cure ageing. For example, there has been a lot of studies done on centenarians. We study their genes and identify why they live longer than average human beings. We also research ageing on some model organisms: naked mole-rats (The term naked means it doesn’t have body hairs, not because it doesn’t wear clothes) and nematodes (C. elegans). These two are some of the best model organism scientists use for anti-ageing studies.

We can’t directly translate results achieved on model organism into humans, but their short lifespan makes it much easier to work on them, especially when you are doing ageing research.

S.No Hallmarks of Ageing Ways to treat Hallmarks of Ageing
1 Genomic instability Elimination of damaged cells
2 Telomere Attrition Telomerase reactivation
3 Epigenetic alteration Epigenetic Drugs
4 Loss of Proteostasis Activation of Chaperons and proteolytic systems
5 Deregulated nutrient sensing Dietary Restriction; IIS and mTOR inhibition, AMPK and sirtuin activation
6 Mitochondrial dysfunction mitohormesis, Mitophagy
7 Cellular senescence Clearance of senescent cells
8 Stem cell exhaustion Stem cell-based therapies
9 Altered Intracellular Communication Anti Inflammatory drugs, Bloodborne rejuvenation factors

1. Genomic Instability⇒Elimination of damaged cells

Damaged cells as a result of genomic stability can be removed by triggering autophagy and the immune system.

2. Telomere Attrition⇒Telomerase reactivation

Telomerase is a small enzyme that repairs telomere. These are active in our earlier stage of life but gets deactivated once we get older. Reactivating them seems a logical approach to solving this problem. The reactivating telomerase is like handling a double-edged sword; a slightly more activation will lead to cancer. Cancer cells have highly active telomerase activity; that’s why they keep proliferating and may lead to an individual’s death. So regulation is the key point here. We have to discover ways to regulate telomerase activity in order to solve this problem. Companies like geron.com are already working on telomere problems.

3.Epigenetic alteration⇒Epigenetic Drugs

Due to Epigenetic changes with age, many genes get upregulated or downregulated due to a change in histone packing structure or a change in methylation of their promoter region. We can provide epigenetic drugs which can undo these changes which will bring back gene expression level to normal.

4.Loss of Proteostasis⇒Activation of Chaperons and proteolytic systems

A protein needs to be correctly folded in order to work properly but with age, this folding mechanisms gets weaker. Misfolded proteins can cause a lot of diseases from Parkinson’s to Alzheimer and many more old age-related diseases. By activating chaperons by activating their promoters by drugs we can again bring proteostasis in baalnce.

5. Deregulated nutrient sensing⇒Dietary Restriction; IIS and mTOR inhibition, AMPK and sirtuin activation

Dietary restriction and prolonged fasting have scientifically proven effects on longevity. Dietary restrictions improve nutrient-sensing as it directly interacts with the Insulin sensing pathway.

6.Mitochondrial dysfunction⇒mitohormesis, Mitophagy

Dysfunctional mitochondria can be cleared by mitophagy so the newer or more efficient mitochondria can take their place and increase the ATP ratio in the body.

7.Cellular senescence⇒Clearance of senescent cells

Clearing old toxic senescence cell is as important as clearing your house. Senescent cells are very toxic to the body, they contain inflammatory agents that cause damage to normal tissues. We can kill senescent cells by specifically targeting then using senescent cells specific properties, for example, senescent cells contain more glyceric acid than normal cells.

8.Stem cell exhaustion⇒Stem cell-based therapies

We can replenish stem cell pools by somatic cell therapies in which we graft stem cells in the body. we can also regenerate stem cells pool by iPSC (induced pluripotent stem cells) in this we provide growth factors to normal cells via viral vectors which can convert normal cells to stem cells.

9. Altered Intracellular Communication⇒Anti Inflammatory drugs, Bloodborne rejuvenation factors

Cells need to communicate with each other in order to work properly, be it endocrine, neuroendocrine or neuronal. As we get old, this communication between cells gets weakened that may lead to many diseases. Then it also makes you more susceptible to infection as immune cells are no longer capable of communicating with each other; that’s why you can understand why older people are more vulnerable to the recent COVID virus.

In modern days due to the development of new technologies and advances in life sciences, we are improving our understanding of physiology better than ever. And it is the tremendous progress we made during this journey that attracted quite the attention of big giants like Google ( Calico, a company supported by Google), and they are willingly investing in this field quite actively, now it’s not far you’ll see visionaries like Elon Musk would start investing in this field further proving their visionary status.

References: 

  1. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-1217. doi:10.1016/j.cell.2013.05.039
  2. Guerville F, De Souto Barreto P, Ader I, et al. Revisiting the Hallmarks of Aging to Identify Markers of Biological Age. J Prev Alzheimers Dis. 2020;7(1):56-64. doi:10.14283/jpad.2019.50
  3. Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of Cellular Senescence. Trends Cell Biol. 2018;28(6):436-453. doi:10.1016/j.tcb.2018.02.001
  4. Folgueras AR, Freitas-Rodríguez S, Velasco G, López-Otín C. Mouse Models to Disentangle the Hallmarks of Human Aging. Circ Res. 2018;123(7):905-924. doi:10.1161/CIRCRESAHA.118.312204
  5. Kenyon CJ. The genetics of ageing [published correction appears in Nature. 2010 Sep 30;467(7315):622]. Nature. 2010;464(7288):504-512. doi:10.1038/nature08980
  6. Martins R, Lithgow GJ, Link W. Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell. 2016;15(2):196-207. doi:10.1111/acel.12427
  7. What is ageing
  8. Evolutionary Theories of ageing 
  9. Damage based Theories of ageing
  10. Curing ageing and science of immortality
Default image
Govind Prakash
Govind is a BS-MS Final year student at IISER Bhopal, he is highly interested in Biogerontology (Biology of ageing). He loves writing articles, blogs and doing creative things. He is also one of the co-founders of scienced.in, he also runs his personal blog website geront.org where he writes about latest biogerontological researches. If you are also interested in Biogerontological researches, You can contact him at govind7x@gmail.com.

Leave a Reply