Top Hallmarks of Ageing and how to affect each of them

Graphic of the 9 hallmarks of ageing

Hallmarks of Ageing are the complex and intra-individual Biochemical changes occurring in living organisms due to biological Ageing that leads to loss of physiological integrity and impaired functioning that make us more susceptible to death.

Hallmarks of Ageing were enunciated for the first time in 2013 to understand the chemistry behind the ageing process. The ageing process is the primary factor that digs into most human diseases, including cancer, diabetes, high blood pressure, fatigue, cognition malfunction, and neurodegenerative disorders.

A "metabolic clock" is responsible for metabolic alteration and diminishes metabolic homeostasis and biological activity. Our genetics and environmental factors can exacerbate the hallmarks of Ageing. Each hallmark manifests the occurrence and accumulation of circumstances responsible for different kinds of age-related pathologies in the human body.

Top Hallmarks of Ageing

The Hallmarks of Ageing determine the difference between chronological and biological age. The most basic 9-hallmarks of Ageing are summarized below:

1. Genomic instability

A common denominator associated with Ageing is the accumulation of genetically damaged cells. Each cell of the human body is composed of the 3-billions letter on the DNA string, except red blood cells define the complexity of our genome. The proper function of the human genome is of utmost importance for the smooth running of our body, but unfortunately, several factors make it impossible to run smoothly. The combination of exogenous factors (radiation and pollution), endogenous factors (oxygen free radicals), biological and chemical characteristics are constantly adamant about destroying the smooth functioning of our genome.

Image of DNA spiral breaking, losing it's data

Up to one million times, the destruction and repairing of DNA in each cell is an eye-opening fact. Although the DNA coding and encoding process can compensate for most of the loss, it loses its function as we age, and the repairing process is not flawless.

Genomic instability related diseases:

Accumulation of damaged DNA cells causes premature-aging ailments like Bloom syndrome and Werner syndrome. Cancer is also one example of irreparably damaged DNA cells both in humans and mice. Neurodegenerative diseases and Neuro-muscular diseases are results of hallmarks of Ageing.

Addressing Human impact:

The risk of Genomic instability can be affected by avoiding exposure to ultraviolet rays, carcinogens and by finding a way to curb malnutrition. Exposure to chemicals other than carcinogens like heavy metals, acrylamide, benomyl, and quinone contributes significantly to senescence markers.

2. Telomere shortening

During the accumulation process of DNA, telomere regions are more susceptible, which are gradual nucleotide sequences in linear chromosomes and are associated with proteins. Their job is to prevent the end region of chromosomes from degeneration and ensure the linear strand instead of the double strand.

 Graphic visualisation of shortening telemore

The absence of telomerase leads to repetitive DNA deterioration, leading to telomere shortening and ultimately resulting in apoptosis.

Telomere shortening related disease:

The development of premature diseases like Pulmonary fibrosis, aplastic anemia, dyskeratosis congenital are the results of telomere shortening due to the deficiency of the shelterin component. Excessive loss of telomere leads to a lack of regenerative tissue and speeds up the ageing process.

Research studies implicate a direct relationship exists between the telomere length, senescence, and Ageing. Studies on mice involved that the short telomere length decreases the lifespan while the long telomere increases. Similarly, Telomere attrition is considered as the significant reason for increased mortality in young humans. So, activation of telomere can revert the ageing process. Turning off the Telomerase enzyme in humans is responsible for preventing telomere shortening and restoring its length.

Addressing human impact:

We can reduce the risk of telomere shortening by:

  • Dietary restriction, a diet rich in fibers, plenty of antioxidants, and low protein are the natural antidotes for telomere shortening.
  • Saying goodbye to smoking and staying in a pollution-free environment works wonders to reverse the senescence markers.
  • Exercise, suitable physical activities, and a tension-free environment can reduce the risk of telomere shortening to an optimum level.

3. Alteration of epigenetics

The long sequences of DNA strands are wound around histones which consist of cranks, levers, and handles to coil the DNA strands and turn them on and off. These cranks, addresses, and levers make your epigenomes. A significant alteration in epigenomes is observed as we age, levers are lost, or shift abruptly. The Sirtuin removes the epigenetic handle, and you can surprisingly adjust lever and handle in your epigenomes by excessive exercise, pharmaceutical factors, lifestyle, and diet.

MicroRNA illustration

The epigenetics as a hallmark of Ageing is observed in mice, yeast, flies, and worms. Studies suggested that dietary supplements can alter the epigenetic changes in mice and sirtuin deficient mice were more susceptible to Ageing than those with abundant levels of Sirtuin.

Epigenetic alteration-related diseases:

The progeroid syndrome is mainly observed in people with epigenetic perturbation. STIR6 is responsible for the healthy long lifespan in mice; as we age, the amount of NAD in our body decreases, which is used as a cofactor by sirtuin enzymes. So, loss of NAD means loss of Sirtuin, and loss of Sirtuin means accelerated Ageing.

Addressing human impact:

A human can affect or ward off epigenetic alteration senescence marker in different ways.

  • Healthy lifestyle
  • Reduce tobacco smoking
  • Reducing Overnight working
  • Reducing alcohol consumption
  • Pollutant free environment
  • Avoiding Constant obesity
  • Avoiding Stress
  • Avoiding Different organic and inorganic chemicals

4. Proteostasis loss

Genes must build up proteins that are the heart and soul of every living organism. The maintenance of proteins means the maintenance of almost the whole body structure. The production and abundance of protein structure are termed proteostasis.

Impaired protein homeostasis or proteostasis are involved in various age-related diseases. To ensure stabilization of exact folding of protein chains like heat shock proteins and keep an eye on protein degradation mechanism by lysosomes and age-related proteotoxicity regulators is the job of proteostasis mechanism.

So, the management of all of these mechanisms simultaneously restores the misfolded polypeptide chains, remove or delete them altogether to avoid the accumulation of degraded parts and for continuous renewal of intracellular components both in mice and in humans. Clumping together of misfolded proteins results in the production of toxicity in the body.

Loss of proteostasis-related diseases:

Loss of proteostasis, chronic misfolding of polypeptides, and aggregation of damaged components result in the surge of age-related pathologies such as cataracts, Parkinson's disease, and Alzheimer's disease.

Addressing human impact:

How can we affect or avoid the risk of Proteostasis loss-the Hallmarks of Ageing? It's simple, the main reason behind the proteostasis loss senescence marker is stress, so enrich yourself with a happy and jolly environment to stay away from stress and enhance your lifespan. Moderate pressure is also beneficial for proper body functioning but not acute stress.

5. Abrupt nutrient sensing

The cell's ability to recognize and distinguish a particular chemical and its response to the concentration of essential macronutrients in the body is called nutrient sensing. At the time of abundance of macronutrients, anabolism starts through the mTOR mechanism. The scarcity of nutrients and energy indicates that AMPK should switch off the mTOR mechanism to store the number of nutrients left wisely.

In growing organisms, the mTOR mechanism is fully activated, while it declines to some extent in adults. It's the rule of nature that the access of nutrients in the animal body encourages them to grow and reproduce. Still, they are more focused on survival, repairing, and maintenance in the scarcity of nutrients.

Research studies were drawn by forcibly activating the mTOR mechanism in mice, and it implicated the acceleration of the ageing process and the mice more susceptible to cancer. But the nutrient restriction and rapamycin administration resulted in longevity in mice, flies, and worms.

Addressing human impact:

We can reduce the risk of Hallmarks of Ageing through deregulated nutrient sensing through Fasting, reducing nutrient contents in our food, and by medication.

6. Mitochondrial dysfunction

Different cells in the human body comprise almost 20-30 mitochondria (the cell's powerhouse), which convert carbon and oxygen into ATP and carbon dioxide. Biogenesis and free radicals in the mitochondria are responsible for the destruction of all cells that come in their way, and this abrupt working of Mitochondria results in Mitochondrial dysfunction.

3D image of a mitochondria in a human cell

ROS are involved in the ageing process, and the decrease in the number of ROS can be thought to provoke longevity. Sometimes ROS doesn't affect health, and sometimes these are responsible for the cellular signalling stress. The stress response can result in the maintenance and robustness of many organs and tissue. So, it's must to keep the amount to a moderate level in the Goldilocks zone.

Mitochondrial dysfunction deteriorates the inter-organellar crosstalk and cellular signalling by affecting mitochondrial membranes such as the outer mitochondrial membrane and endoplasmic reticulum. Mitochondrial dysfunction is the root cause of degenerative bio-energetic and depletes the respiratory chain.

Addressing human impact:

Alternate-day Fasting can restrict these senescence marks, and endurance training can enhance an individual's lifespan to a remarkable extent. Fasting and endurance training are potent triggers to facilitate autophagy and regeneration of new cells.

Image Person doing endurance training

7. Cellular senescence

The cell exiting without dyeing by becoming dormant or stopping functioning from the cell cycle is categorised under cellular senescence. Various factors are responsible for cellular senescence, including telomere shortening, stress, Damaging of DNA. The senescence in the immune system works to get rid of damaged cells to restore the actual state of the cells.

The amount of cellular senescence is proportional to the age of humans and inflammatory markers, which are culprits behind the Hallmarks of ageing. These are otherwise active before entering into the dormant state. Unfortunately, there is no way to get rid of them; they just keep accumulating as we age and result in the surging of toxic diseases. If we somehow find a way to clear the senescence cell and get rid of it, we can expect a sharp increase in lifespan.

Telomere attrition can trigger cellular senescence along with many other factors. For years scientists were confused about either cellular senescence is the reason behind cancer or not. Destruction of senescence cells was trigged experimentally in mice to observe the effect on life span, and luckily, results were evident in the form of an increase in lifespan.

Addressing human impact:

A healthy diet, medication, and natural lifestyle can reduce the risk of cellular senescence.

8. Exhaustion of stem cells

Undifferentiated cells that profligate continuously are categorised under the name of stem cells. Exactly after fertilisation, the embryo is entirely composed of stem cells. As the fetus grows gradually, the differentiation and the division of stem start, and each cell performs its specific function. Stem cells in adults are only limited to the areas involved in the division, demand replenishment (hair follicles, red blood cells, and immune cells) in a continuum or that wear with time (intestine, skin, mucous, and lungs). So, our stems cells are exhausted as time passes which are responsible for the acceleration of the ageing process.

The ageing process can be reversed in organisms by rejuvenating stem cells in humans and mice blood. Only healthy stems can replicate, opening the doors for longevity.

Addressing human impact:

Dietary intervention, calories restriction, and no obesity are the keys to curb this Hallmark of Ageing.

9. Alternation in intercellular communication

The working of different tissues and cells in an orchestrated manner is mandatory for the proper functioning of the body. The signal molecules travel through the bloodstreams to others to communicate with them.

The profiling systems of the cell to cell communication are affected by signalling biomarkers, including "inflaming." The normal inflammation can trigger the immune system to repair the damaged area, but their constant and long-term residence in a particular area can damage the immune system cells.

Addressing human impact:

Calories restriction and Parabiosis-mixing of the circulatory system of two different individuals can pave the way to an unaltered intercellular communication. This senescence mark is strongly associated with other Hallmarks of Ageing, so to treat it, the better option is to look for the treatment of other Hallmarks.

Conclusion

Every one of us has to face some of the Hallmarks of Ageing at different stages of our life, but the rate and the effect of different senescence markers are different in other individuals. We can't stop the ageing process, but the wise man is who lives a healthy life, with a minimum influence of different Hallmarks of Ageing. We can reduce the risk of other Hallmarks of Ageing by adopting a healthy lifestyle, moderate diet, exercise, happy life, and saying goodbye to alcohol and smoking.