What Causes Ageing?
The 9 Hallmarks of Ageing
What makes us age and get sick as we get older?
Many of us hope to live longer, as long as those extra years are filled with good health. Scientists studying anti-ageing have made significant progress in not just figuring out how ageing happens, but also in finding ways to slow it down and let us enjoy more years without dealing with long-lasting illnesses.
An important milestone came in 2013, when a group of authors led by Carlos López-Otin, Professor of Biochemistry and Molecular Biology from the Universidad de Oviedo in Spain, published a landmark study called the Hallmarks of Ageing.
The paper has become one of the most widely-quoted and highly regarded papers in the scientific community and spurred many scientists to conquer the ageing problem.
Geroscientists aim to extend our lifespan by comprehensively studying and addressing the ageing process. Their goal is to offer us additional years of life with a reduced risk of the chronic ailments that often come with growing older, like cancer, heart disease, Alzheimer’s, Parkinson’s, and various forms of dementia.
The Hallmarks of Ageing
López-Otin’s paper systematically catalogues the nine processes which cause us to age — called the hallmarks of ageing — listing them as:
1. Genomic instability
DNA damage occurs all the time, and our cells have repair mechanisms to correct these errors. As we age, however, our repair mechanisms fail to correct this damage, and mutations accumulate, leading to ageing and disease. Cumulative DNA damage leads to genomic instability, a foundational hallmark of ageing.
2. Telomere attrition
Looking very much like the plastic tips on the ends of shoelaces, telomeres are the protective caps on the tips of our chromosomes. They progressively wear down as we age, and telomere attrition is a primary hallmark of ageing.
Telomeres are repeated patches of DNA that maintain the stability of our chromosomes and protect our genetic data. Telomeres also act as a biological clock in our cells. Each time a cell divides, its telomeres get shorter, until the cell either undergoes a form of cell death called apoptosis or becomes senescent.
Unfortunately, when telomeres wear away — due to ageing or environmental stresses — our DNA becomes vulnerable to degradation. Shorter telomeres cause genomic instability and may contribute to developing cancer.
3. Epigenetic alterations
Epigenetic changes are an important hallmark of ageing and have received much attention lately. Researchers recently discovered epigenetic clocks that may control how we age.
The epigenome is the master program which controls our genetic code. An epigenetic programme makes a series of temporary changes to our genome, and runs the show by turning genes off or on, and controlling protein production in particular cells.
Our environment influences our epigenome and modifies it via epigenetic changes. As we age, our cells are continually under assault by toxins and other stressors which change the epigenome.
4. Loss of proteostasis
The decline in the protein quality of our cells, called the loss of proteostasis, is a fundamental hallmark of ageing. Our bodies have defences against cellular stress. However, after decades of repeated assaults by stressors such as free radicals and other toxins, the proteins in our cells become damaged or misfolded.
5. Deregulated nutrient-sensing
As we grow older, metabolic changes lead to deregulated nutrient sensing, a compensatory hallmark of aging. We have multiple nutrient sensing pathways to make sure that our bodies take in just the right amount of nutrients — not too much, not too little. However, the accumulated decades of assaults damage our nutrient-sensing pathways.
6. Mitochondrial dysfunction
As our cells age, the mitochondria start to lose their integrity due to the build-up of free radical damage. Degraded mitochondrial function leads to decline in our cells and tissues and an increase in a type of cell death known as apoptosis.
Damaged mitochondria produce even more free radicals which damage the mitochondria even further, leading to a weakened body. This mitochondrial decline is especially noticeable in tissues with high energy demand such as the heart or the brain.
7. Cellular senescence
As our cells age, they lose their ability to divide and become senescent. Researchers define cellular senescence as the point at which our cells stop dividing due to damage or lack of supplies. When we are young senescent cells are thought to be cleared by the immune system, but when we are older, they stick around secreting inflammation-stoking molecules that damage our bodies further.
Because cellular senescence is an important hallmark of ageing, geroscientists have developed compounds which clear senescent cells from the body.
8. Stem cell exhaustion
As we age, our stem cells eventually lose their ability to divide, leading to stem cell decline as an integrative hallmark of aging. As our stem cells go into decline, our bodies are unable to replace the stem cells that have migrated, differentiated, or died. As a result, we show outward signs of ageing and an increase in age-related disorders.
9. Altered intercellular communication
As our cells grow older, their communication with other cells becomes dysfunctional leading to an increase in chronic inflammation and unhealthy hormonal changes.
The ageing cells in the organs play havoc with the body, changing the quality and quantity of hormone instructions they transmit throughout the body.
The biological processes underlying ageing are complex and interrelated. By understanding the hallmarks of ageing in greater detail, geroscientists can get closer to the goal of developing interventions that retard the ageing process.
López-Otin defined the hallmarks based on how well they meet specific criteria, such as a) a particular hallmark must manifest itself during normal ageing; b) if researchers experimentally aggravate the hallmark it should accelerate ageing and finally, c) preventing or blocking the hallmark should retard ageing, resulting in increased lifespan.
Summary: The hallmarks of ageing is a landmark paper which pinpointed the underlying causes of ageing and spurred geroscientists to develop lifespan-extending drugs.
This report provides an update of some of the significant accomplishments in longevity research since the paper was published. [This article first appeared on the LongevityFacts.com website, Author: Brady Hartman.
Carlos López-Otín, et al. The Hallmarks of Aging. (2013) Cell, Volume 153, Issue 6, 1194–1217. Available Online.
