Inflammation and the aging process

by Ryan Wallis, PhD

Aging and Disease

Imagine a world where everything you do is missing just a little piece and as time goes on you start to lose sense entirely.

This is the devastating world of neurodegeneration, a collective term for diseases which include Alzheimer’s and Parkinson’s. Conditions like these have an enormous impact on both the individuals who suffer from them and their families, who must watch their loved ones ebb away into a shell of their former selves. These conditions are as cruel as they are debilitating and, alarmingly, they are on the rise (Alzheimer’s Association, 2017).

In fact, almost all conditions associated with ageing are becoming more common. This is because we, as a population, are getting older. The World Health Organisation predicts that, by 2050, two billion people worldwide will be over the age of 65 (World Health Organisation, 2019). This will be the result of the enormous strides we are currently taking in medicine, sanitation, nutrition and education. However, the consequence of this is an unprecedented burden on our health and social care services, a problem which is only set to get worse. Age is a major risk factor for an extensive list of conditions, including: Alzheimer’s, Arthritis, Cancer, Diabetes, Heart Disease, Osteoporosis, Parkinson’s, Stroke and many more (Munoz-Espin and Serrano, 2014). Individually, all of these areas have gained considerable interest from the research community, but perhaps a broader approach will allow us to understand common factors within them all.

Gerontology: The study of aging

Ageing research aims to better understand the biological processes which lead to the fragility and susceptibility to disease which we see in the elderly (Campisi et al., 2019). It is not looking for a fountain of youth, a way to turn back the clock, but rather a means of extending the time an individual is disease free – their so-called “Healthspan”. The field aims to uncover the processes which lead us to age and, as with most areas of biology, the secrets are locked away within our cells.

Cellular Aging

The idea of “cellular ageing” was first described by Leonard Hayflick in 1961. He saw that cells grown in a flask could only divide a finite number of times before they entered a semi-dormant state he termed “Senescence” (Hayflick and Moorhead, 1961). These cells often look very different from their growing counterparts, becoming large, flat and irregularly shaped (van Deursen, 2014). These changes in the cells’ appearance led researchers to ask, “What might these cells be doing in the body?”

Replicative senescence

To find the answer to this question we must first understand why cells become senescent. Before cells divide, they go through a process called DNA Synthesis. Through this, cells duplicate all the genetic information which allows them to carry out their functions in the body. This allows two new daughter cells to be generated from the original, each with an identical set of genetic code (Schafer, 1998). Molecules of DNA are usually wound up into long, tight packages known as chromosomes, which prevent the DNA becoming a tangled mess. At the end of these chromosomes is a protective cap called a Telomere, which works a bit like the plastic tip on the end of shoelace (which I recently discovered is called an aglet - who knew!). The telomere is a repeating sequence which protects the important coding regions of the DNA molecule during replication. However, every time a cell divides and goes through DNA synthesis, a little piece of the telomere is chipped away (Xu et al., 2013). This, eventually, shortens the telomere to a level which sets off alarm bells within the cell, alerting it to the fact that further DNA synthesis could lead to DNA damage and the possibility of a cell becoming cancerous (Fagagna et al., 2003). To avoid this, the cell stops dividing and becomes senescent (Sharpless and Sherr, 2015).

Cytokines produced during senescence

The senescent cell then produces a complex cocktail of inflammatory cytokines and tissue remodelling agents including: IL1α, , IL-6, IL-8, MMPs and growth factors, which are collectively termed the SASP – the senescence associated secretory phenotype (Coppe et al., 2008). The SASP then recruits cells from the immune system, to clear away the senescent cell (Xue et al., 2007; Kang et al., 2011; Yun, Davaapil and Brockes, 2015). This cell is quickly replaced as neighbouring cells continue to divide, maintaining the overall number within the tissue. So, we know that cells become senescent as a protective response to stresses which may cause DNA damage or cancer. What then, has senescence got to do with ageing?

The role of senescence in ageing and inflammation

As we age, our immune system becomes weaker and less efficient at clearing unwanted senescent cells in response to signals from the SASP (Kang et al., 2011). This causes senescent cells to build up in our tissues as we get older (Ovadya et al., 2018). At the same time, the number of cells which are growing and can take the place of the now senescent cells becomes less and less, limiting the regenerative capacity of the tissue and, ultimately, contributing to fragility and poor wound healing (van Deursen, 2014). It has also been discovered that exposure to the SASP of senescent cells can cause neighbouring cells to become senescent themselves (Acosta et al., 2013). This becomes a problem when the cells aren’t being cleared, as it causes senescence to spread. As senescence spreads, it causes a low-level (but chronic) state of inflammation, which researchers believe could be behind the myriad of inflammatory, age-related diseases (Munoz-Espin and Serrano, 2014). Due to discoveries like this, researchers are beginning to explore therapeutic strategies with the hope of combating many conditions which are experienced by the elderly, through the modulation of senescence (Kirkland et al., 2017).

Senolytic Drugs

It is important to always keep in mind that senescence actually has a very important, positive function – it protects us from cancer (Campisi and D’Adda Di Fagagna, 2011). It is for this reason that we cannot simply turn off the senescence response by targeting the signals which drive it. To avoid this issue, one strategy could be to develop drugs which selectively kill senescent cells, clearing them from the body when it cannot do so for itself (Xu et al., 2018). Exciting work in this area has been carried out in naturally aged mice, where a method of removing senescent cells led to both the alleviation of age-related diseases and (remarkably) an increase in lifespan of up to 35% (Baker et al., 2011). This ground-breaking work has sparked a wave of interest in the field of senescence and rejuvenating medicine, with the first generation of so-called “senolytic” drugs currently undergoing clinical trials (Justice et al., 2019). The greatest problem for any new approach lies in identifying which cells in the body are senescent and designing a drug which only targets those cells, limiting damage to healthy cells. Ideally, any new therapy would identify and target a marker which is exclusive to senescent cells but not involved in the process of becoming senescent (Kirkland et al., 2017). This is because we need to maintain the protective mechanism against cancer, or else risk causing more harm than good.

So where do we go from here? Senescence is difficult phenomenon, as it underlies the body’s natural protections against cancer but may contribute to a huge variety of diseases. These diseases are particularly associated with ageing, where senescent cells are less efficiently cleared by the immune system and cause an inappropriate inflammatory response. Many of these conditions (as demonstrated in the first two paragraphs) are some of the most debilitating and heart-breaking, which not only ruin what should be our golden years, but do so slowly and remorselessly, with very little treatment available. Senescence research presents an exciting opportunity to take a big stride in understanding what causes these conditions and may offer a new route to therapeutic intervention.

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