September 24, 2021

I, Science

The science magazine of Imperial College

Yodit Feseha tells us how ageing works and if it’s possible to reverse it (taken from the latest issue of I,Science magazine)
Turritopsis Dohrnii, the immortal jellyfish
Turritopsis Dohrnii, the immortal jellyfish

The lifespan of all living organisms varies tremendously; some have lifespans measured in hours, some are measured in years and some stretch to centuries. There are even organisms that have achieved seeming immortality.

Humankind’s continual reach for knowledge has allowed us to develop treatments for diseases which, in the past, would have claimed many lives. With our increasing understanding of the human body, is immortality achievable? This article explores the cause of ageing and how scientists are proceeding to further extend our life span, which could possibly lead to immortality in the future.

Flies such as the mayfly can live up to two hours, lobsters can live up to 50 years. Giant tortoises have an average life span of 100 years and the bowhead whale has an average life span of 200 years. Remarkably the naked mole rat is the longest living rodent living up to 31 years. Once Turritopsis Dohrnii, also known as the immortal jellyfish, has reached adulthood and reproduced, it can regenerate itself, starting its life cycle all over again.

What happens as we age?

From our early 20s we already start losing our brain cells. From our late 20s the activity of the heart, lung and kidney starts to decline. Our memory, bones and muscles become weaker. Our skin loses its elasticity, becoming wrinkly. The immune system is weaker and becomes more susceptible to infection. Reduction in the pigment melanin results in grey and eventually white hair.

Free radical theory of ageing

One theory of ageing is that free radicals decrease the lifespan of an organism by influencing ageing associated diseases such as cancer, stroke, diabetes and many more. A free radical is an atom, molecule or ion that has unpaired electrons causing it to be highly reactive towards other substances and itself. As we age, free radicals accumulate in our bodies as the result of several factors such as the breakup of large molecules, ionising radiation, heat and chemical reactions. On a molecular level, the human body therefore accumulates free radical damage to the cell as it ages.

Accumulation of free radicals has been implicated as the cause of DNA, protein and lipid (fat) damage. This damage can lead to mutations in the genome causing various diseases and cell death.

In contrast, free radicals can also assist immune cells such as macrophages in fighting infection and are also associated with the cell communication process.

Mitochondrial theory of ageing

B0003654 An isolated mitochondrionAn older individual has a higher amount of damaged/mutated DNA, oxidised proteins, and lipids (which are essential for energy storage, cell signalling and structural components of the cell membrane). The mitochondria (energy producers in cells) in particular are more susceptible to this type of damage as they are more exposed to it. They also have a less efficient DNA repair mechanism compared to nucleic DNA. A cell can contain hundreds of mitochondria which are involved in energy production by synthesising adenosine triphosphate (ATP); a high energy molecule that stores the energy we use.

Oxidative substances, by-products of the ATP synthesising process, are released into the mitochondria and the cell. Those oxidative substances, which can include non-free radicals can cause damage to the cell, including the essential enzymes. As a result, they can damage the function of the mitochondria, leading to a low level of ATP production.

This is one of the main causes of ageing, as the cell cannot function well with insufficient energy. Thus, oxidative substances lead to age related diseases causing a shorter lifespan. Interestingly the longest living rodent, the naked mole rat has the ability to slow its metabolism, thus preventing oxidative damage in cells.

Reducing the number of calories eaten in mice and in humans has been shown to result in a decline of oxidative substances and therefore less damage to cells. This is because a high calorie diet can increase the level of free radicals produced in the mitochondria from metabolism. Therefore it is evident that a healthier lifestyle, with a low calorie diet and plenty of exercise can lead to a longer life.

The aglets of our chromosomes

TelomereTelomeres are often compared to the plastic tips of shoelaces (aglets). They are a repeated DNA base sequence found in the tip of chromosomes which prevent chromosomes from fusing their tip ends with each other. During every cell division the telomeres lose 25-200 bases of their sequence. Once this reaches a certain length, the cell can no longer replicate and undergoes programmed cell death.

These telomeres are regulated by an enzyme known as telomerase. This enzyme can elongate the telomere’s sequence and is highly active during developmental stages. The absence of telomerase in adult cells, leads to an ageing body.

So why don’t we just inject ourselves with telomerase? Well, telomerase is associated with cancer cells. HeLa cells (an ‘immortal’ human cell line isolated in cervical cancer patient, Henrietta Lacks) are used often in experimental biology, and do not suffer any form of cell death due to the highly active presence of telomerase.

The reversible process of ageing?

Theories of ageing explain its process, but it has been hard to pin down how it can be reversed. Consumption of anti-oxidants, for example, may reduce oxidative substances in the cell but excessive amounts can also cause harm to the body. However, Professor David Sinclair and his research team at Harvard University have investigated an ageing process that is reversible.

The nucleus encodes genetic material that is useful for the mitochondria, which in return generate energy the nucleus requires. This communication between the two parts is essential for a healthy functioning cell. In the bodies of younger people, there is very good communication between these elements but this gets weaker as the cell ages. This is caused by a low level of nicotinamide adenine dinucleotide (NAD+) in the cell. This causes certain enzymes dependent on NAD+ involved in the interaction between mitochondria and the nucleus to not function properly. For example SIRT1 (NAD+ dependent deacetylase) is an enzyme important for this communication and it has been observed at a low level in older laboratory mice as the result of low NAD+ level.

Activating SIRT1 artificially in mice extended their life span significantly. The same mice who saw their life span extended in this way also experienced an improved metabolism and less physiological and cognitive damage. In addition, fewer age related metabolic diseases were experienced later in life and mice were generally healthier. The artificial activation of SIRT1 also resulted in regeneration and restoration of the heart muscles, whilst mitochondrial activity was restored. A drug has been developed to do exactly this in humans, which currently is undergoing clinical trials.

If the outcome of this is similar to that seen in mice, extending human lifespan might be possible in just a few years. Our understanding of many biological processes has advanced enormously in the last ten years, in particular because advances in technology have changed how we can analyse biological data. So why can’t immortality be achievable in the future?

Yodit Feseha is studying for an MSc in Human Molecular Genetics

Images: Giant Tortoise; Turritopsis Dohrnii, the immortal jellyfish: World Register of Marine Species, Peter ShuchbertMitochondrion: David Furness, Wellcome Images; Telomeres: Wikimedia commons