How Do We Age?

Benjamin Franklin has once stated that there are only two things certain — death and taxes. We won’t talk about the completely unavoidable thing and will instead speak about death. Currently, the main reasons behind the death are aging-related diseases. The most important of them are cardiovascular diseases and cancers. They are responsible for half of all deaths in 2016. Therefore, aging research is so important.

To fight the process of aging, we should understand the processes behind it, first of all. Early theories considered aging to rely on a single mechanism. With time, we understood how much more complex it really is.

The first aging research framework was presented in 2003 by Aubrey de Grey. Strategies for Engineered Negligible Senescence (or SENS for short) were vital to the further development of gerontology that led to the creation of one of the most renowned gerontology organizations — SENS Research Foundation.

The most up-to-date classification is provided in the 2013 article ‘The Hallmarks of Aging’ published by the team of Carlos López-Otín in Cell. This article aimed to be a roadmap for the aging research just as previously published ‘The Hallmarks of Cancer’ became a roadmap for cancer research. It is the most cited article in the gerontology field. With 3300+ citations it is cited almost twice a day.

Authors state that there are nine distinct hallmarks of aging: processes that, while combined, lead to the age-related diseases. These hallmarks aren’t of the same weight and can be split into three groups:

Primary hallmarks: mechanisms that are the initial reason behind the aging. This is how our organism responds to continuous damage it gets. They include:

  • Genomic instability
  • Telomere attrition
  • Epigenetic alterations
  • Loss of proteostasis

Antagonistic hallmarks happen in response to the primary hallmarks and aren’t harmful in their normal state. However, when they become chronic they start to contribute to the overall damage:

  • Deregulated nutrient sensing
  • Mitochondrial dysfunction
  • Cellular senescence

Integrative hallmarks are the result of combined effect of primary and antagonistic hallmarks. They are responsible for the systemic aging and are the most damaging for our organism:

  • Stem cell exhaustion
  • Altered intercellular communication.

1. Genomic instability

Factors from out- and inside our body damage DNA each day. Our cells can fight these mutations, but only to a certain degree. As most mutations are harmful, their accumulation leads to the cellular dysfunctions and possibly to cancer. Many aging-accelerating diseases, such as Werner and Bloom syndromes, are linked to the failures of repair systems. For a cell to become cancerous, it needs to get several mutations in specific spots. As our ability to fix our genome drops with age, the risk of cancer rises.

2. Telomere attrition

Telomeres are the DNA fragments at the end of the chromosomes. They do not carry genetic information but are shortened with each division. After all the telomeres are gone (the number of divisions it takes differs depending on the cell type and is called Hayflick limit), the cell starts to cut its own genome and either self-destructs or becomes dysfunctional (senescent).

3. Epigenetic alterations

Epigenetic alterations are functional changes in DNA that are heritable but aren’t direct modifications of genetic code. They include DNA methylation and histone modification. The study of these mechanisms started only recently so it is hard to pinpoint the exact level of connection between epigenetics and aging. However, there are already functional epigenetic clocks that can accurately predict the biological age.

4. Loss of proteostasis

Proteostatis is a constant state of proteins in organism. Cells need proteins to have correct spatial conformation to work. Conformational stability is assured by an array of enzymes, most importantly chaperones and proteases. Proteins receive damage just as DNA does, and this damage accumulates as well. Badly folded proteins can lead to Alzheimer’s and Parkinson’s diseases, and various other conditions.

5. Deregulated nutrient sensing

Excessive consumption leads to obesity and accelerated aging. Calorie restriction (CR) is one of the most well-known methods that can lead to longer life in many mammals.

Moreover, nutrient sensor proteins play a huge role in aging. For example, a change in Insulin-like Growth Factor-1 (IGF-1) levels leads to decreased longevity in mice (both low and high levels were detrimental). Many of the nutrient-sensing proteins, such as APMK and mTOR are known targets for geroprotector drug candidates.

6. Mitochondrial dysfunction

In case you didn’t know, mitochondria is a powerhouse of the cell. It synthesizes ATP, a substance that acts as an energy source for almost all processes in living organisms. However, as many powerhouses, it produces unwanted side products — reactive oxygen species (ROS). ROS harm the genome and the proteins of mitochondria. This damage leads to the underproduction of ATP. Just as cities cannot exist without electricity, organisms cannot survive without ATP.

7. Cellular senescence

Cellular senescence is directly linked to the telomere attrition. As cells reach their Hayflick limit, they normally undergo autophagy (self-destruct mechanism), but some don’t. These cells become senescent. Normally the immune system can deal with senescent cells but they become more prevalent as the time goes.

Even older people have small amounts of senescent cells. These cells, however, can halt the functioning of entire tissues, provoking inflammation. Such chronic inflammation greatly accelerates the overall decline of the organism.

8. Stem cell exhaustion

Stem cells are the building blocks of our organism, progenitors of each cell we have. They help us to repair the cellular damage and continue to operate normally. However, the rate of damage we get accelerates while our ability to replenish stem cells falls. This inevitably leads to the functional decline in our organism. This especially affects the cardiovascular system.

9. Altered intercellular communication

Aging also happens on the intercellular level. Accumulated damage affects the communication between cells, mostly in the form of inflammation. ROS is also an important mechanism in intercellular aging. Altered intercellular communication leads to an array of diseases, mostly immune and neurodegenerative.

Aging research is only the first step on the road to creating effective pro-longevity therapies:

  • stem cell therapies to replenish our stem reservoirs
  • anti-inflammatory drugs to combat chronic inflammation
  • expression of telomerase, a telomere-prolonging enzyme
  • senescent cell clearance with senolytic drugs

Gerontology is still a young science and there is much more to be discovered. Now, the best strategy for those who want to live longer is to study their organism. Regularly visit your healthcare specialist, control your biomarkers and get to know your genetics to find out the optimal course of actions for your personal longevity.

Sources:

http://www.cell.com/cell/fulltext/S0092-8674(13)00645-4

https://ourworldindata.org/causes-of-death

http://www.sens.org/

http://www.cell.com/abstract/S0092-8674(11)00127-9

https://www.sciencedaily.com/releases/2011/03/110316113057.htm