They are super-heroes. They are supposed to protect us from evil. But, when they grow older, does it affect their judgement? Do they do more damage than help? Meet the immune cells in health and ageing. What happens to them as we age? Why do we call for them more often? What happens to their superpowers as we get old? Can they enlighten us in our quest for elixir of life?

An old an angry immune cell roaming around in inflamed tissue
Image by Eneas De Troya | CC BY 2.0

Recap

In the previous episodes we explored the role of DNA damage and repair in ageing. In the next episode, we also explored the role of mitochondria in ageing. We found that damage in the cells accumulate over time. And the ability of cells to repair the damage declines with age. We saw how mitochondria contributes to the damage as well - its function declines with age and it produces more ROS. We also saw some evidence that ROS can act as a two edged sword and ROS associated damage might not be all that is there. Mitochondrial renewal goes down and these aged inefficient mitochondria which are more prone to causing cell death and impede stem cell function, accumulate. We figured that caloric restriction and its mimics act by not only improving DNA repair but also by reducing the source of damage. But until now we mostly focused on damage that happens within cells and originates from within them. But we have not paid attention to tissue damage and damage that occurs from messed up interaction of cells. Hence, today we are going to look at the ageing immune system and its contribution to ageing of an individual.

Ageing - a story of thousand wounds!

I had previously touched on this topic in blog post on contribution of inflammation to type 2 diabetes. We saw there that chronic low grade systemic inflammation causes type 2 diabetes. But, we also saw that this inflammation increases with age; and, it also correlates with thin old individuals who get type 2 diabetes. Usually, inflammation occurs when there is a wound or a pathogen. The first responders, the cells of innate immune system (macrophages, neutrophils, etc) come to site of injury or infection and take measures to prevent further damage. However, if inflammation persists chronically in the tissue it may cause tissue damage (see these blogs to learn more about wound healing and fibrosis). You can think of an old age body as a system which has endured many wounds over the course of time. Some mental, some physical. Some external and visible, but others internal and silent cellular stresses. Some that came with lifestyle choices, but others that happened as wear and tear to the body and were inevitable. All of these wounds calling for help from superheroes of immune system. But, why do these superheroes eventually lose the war? Let's see

What are they fighting against?

A brief infographic of factors that can contribute to chronic low grade systemic inflammation
by @sciecneblocks

Bad lifestyle choices may accelerate chronic inflammation

But, this rather gets us to a very interesting question, what started this low grade inflammation in first place? Well one factor can be lifestyle choices - the food we eat, cigarettes we smoke, infections we endure, LDL-cholesterol in blood, fat we gain or stress we ignore. But, it occurs in mice models too, whose life choices in a lab cage are much less fucked up than ours (Tomay et al., 2018). Also, it has been observed in literature, that even after taking care of lifestyle factors, the systemic low grade inflammation occurs anyway. This hints that there are other innate factors at play (Sandana et al., 2018). So overall, lifestyle does play a crucial role in how gracefully we age and what will be our inflammatory profile. But, they are more of an add on, than being the sole reason.

The senescent cells accumulate and call for help.

We already saw earlier that aged mitochondria promotes ageing. One of the source of chronic inflammation can arise of many cells accumulating damaged mitochondria and even producing more reactive oxygen species causes damage in cells and the tissue. The damage is recognised by nearby cells which causes them to send signals - inflammatory cytokines - which calls for recruitment of immune cells.

In fact , the cells that have more dysfunctional mitochondria and produce more ROS in body are the senescent cells. The senescent cells accumulate in the body with age(He and Sharpless, 2017). In fact, clearance of these senescent cells in mouse models slows down age associated organ damage and even reduce cancer incidence (Baker et al., 2016, Baker et al., 2011)

Not only these non dividing old cells have issues with mitochondria, but they also have their telomeres eroded and higher chances of DNA damage and genomic instability. In an attempt to not go haywire they activate ATM, P53 and P16 pathways. The DNA damage response pathways, such as activation of ATM, also leads to activation of p38MAPK, NFkB and inflammasome (a protein complex in cells that mediates secretion of inflammatory cytokines) pathways (see Miyamoto, 2011, Freeund et al., 2011). NFkB, not only causes inflammation but also promotes survival of these senescent cells. Another way to activate inflammasome, is via damaged mitochondria in these cells activating a protein called NLRP3 (Kauppinen, 2017). The activation of these pathways in senescent cells causes a senescence associated secretory phenotype (SASP). They secrete abundant inflammatory cytokines, such as IL1b, IL8, TNF-alpha and IL6, which then leads to recruitment of immune cells. Moreover, these cytokines and signals has an additional side effect. They cause more nearby cells to become senescent - causing senescence to spread through the tissue - a vicious cycle (Acosta et al., 2013).

Then, these senescent cells also end up having increased activity of retrotransposable elements (RTEs) (the genes of ancient retroviruses (relatives of today's HIV), that became a part of our genome, now called jumping genes because they hop around in our DNA). This causes an increased secretion of interferons which again causes recruitment of immune cells and promote cellular senescence in nearby cell. Now, the jumping of retrotransposons is dependent on an enzyme called reverse-transcriptase, just like for any retrovirus such as HIV. In fact, in curious result Cecco et al., 2019, were able to show that a reverse transcriptase inhibitor could block the age associated inflammation.

But here is the fun part. The invading immune cells are supposed to get rid of these senescent old guys. But the accumulation of these senescent cells with age argues that something overrides it. One possibility is that these old cells over time also tend to increase pro-survival factors. The other being they are generated faster than immune system can handle. Yet another possibility is that chronic inflammation rather promotes senescence further. For instance, in this paper, Jurk et al., show that making a mice with specific deletion of one of the subunits of NFKb causes a chronic inflammatory phenotype in mice. The mice show accelerated ageing and increased accumulation of senescent cells in different tissues. They show that this can be reversed by use of anti-inflammatory drug - ibuprofen or via an anti-oxidant drug. But be careful about use of ibuprofen, as authors did not test it's affect on life-span. Nonetheless, this gives us a hint that not only senescent cells recruit immune cells, but under certain contexts immune cells promote senescent cells in the tissue. Though, more research on this is required to know how it all works out.

Super-heroes age too!

And then the stem cells said - let there be myeloid cells.

Diagram shows how different blood cells arise from hematopoietic stem cells. These stem cells make two progenitors - the myeloid and lymphoid. As we age the differentiation seems to get a bit biased towards the myeloid side.
Image by Mikael Häggström and A. Rad | CC BY-SA 3.0

Anyway, in another scenario the immune system ages itself. As it turns out the hematopoietic stem cells(HSCs), themselves shows some changes with age. If you don't know, these are the stem cells in body that gives rise to all the blood cells. Now, there are two groups of immune cells in the body - the myeloid lineage (neutrophils, macrophages, mast cells -- the innate immune system) and lymphocyte lineage (T cells and B cells -- the adaptive immune system). The basic difference between them is that the former is a much more crude police that are first responders and takes care of all kinds of infections, injury, cellular insults, debris and basically anything that calls out for them. The adaptive guys are more of a specialized task force. They choose their targets and destroy only pathogens and cells containing antigens that they find problematic. It so happens, that as we age the HSCs are more biased towards making the myeloid cells, both in mice and human (Pang et al., 2011, Dykstra et al., 2011). The decreased potency for lymphoid differentiation and increased potency for myeloid differentiation maybe relevant in many age related pathologies. For instance from scarring to solid tumors the cells of adaptive immune system help in healing without causing much tissue damage. But on the other hand persistent inflammation from cells of innate immune cells can promote tissue fibrosis and carcinogenesiscarcinogenesis (but be careful as it is not as black and white as I mention).

Affect of age on super-powers of heroes.

Then the myeloid cells that come to rescue are themselves a little lethargic, in old age as compared to their young versions; even though their numbers aren't affected much (Chatta et al., 1994). On other hand these granulocytes, monocytes and macrophages in aged individual has a different receptor profile. They seem to represent an activated state, while at the same time they have reduced expression of receptors - that help them recognize senescent cells and present antigens to T and B cells (Martinis et al., 2004). This kind of explains why despite high inflammation in tissue old people are more prone to infections and accumulate senescent cells. Think of this situation like making hulk angry without a context, he might unable to tell other avengers about who is the enemy, while at the same time causing unwanted destruction.

Furthermore, their phagocytotic activity is altered. For instance the macrophages in young are much better at clearing up dead apoptotic cells than in old. The neutrophils have similar midlife crisis too (Wenisch et al., 2000). Plus for neutrophils their migration into and out of the tissue is affected, as well (Wenisch et al., 2000).

Imagine it like fate of king's Landing if you watch Game of Thrones. If the neutrophils fail to respond to tissue insult, the insult would damage the tissue. However if neutrophils do come, it's like Daenerys on her dragon, and if it overstays it's welcome, it's going to burn tissue to ashes. The impaired chemotaxis of neutrophils out of the tissue and their prolonged lifespan in the tissue are two such factors that might explain age associated neutrophil inflammation (Oliveira et al., 2016). Moreover, the spiderman like activity of neutrophils of throwing net on their targets is also altered with age. Then, the other myeloid cells such as dendritic cells are also not spared. The cytokines they produce and signalling in the aged innate immune cells is altered, like bigtime. The result - they become more damaging than helpful, overall (Shaw et al., 2013).

The curse of cellular debris

Given that increase in amount of senescent cells, decreased mitochondrial quality - it is not surprising if you find an increase in some cellular debris production and decrease in its clearing up in old individuals. The debris include uncleared dead cells, free DNA from floating around in extracellular matrix and even byproducts of unhealthy mitochondria. Intracellular proteins, N-glycans, ATP and DNA roaming free in extracellular space are recognized as damage associated molecular patterns or DAMPs. Our body is not use to seeing them outside. The resident cells and resident immune cells then activate pattern recognition pathways, that causes these cells to secrete inflammatory cytokines that recruit cells of innate immune system (Poli et al., 2017, Dall'Olio et al., 2013, Feldman et al., 2015). Worse if they are aged immune cells which talk more than they work. Say, a trapped neutrophil which causes more damaged cells and molecules than it gets rid of. Moreover aged immune cells have altered toll like receptor profile,
and hence inefficient pattern recognition and response towards it. That's another vicious cycle, right there.

Decreasing sex hormones and increasing inflammation

Another feature which changes as we age is our hormone profile. For instance the levels of testosterone and oestrogen goes down. These hormones not only maintain our sex life, but may also contribute to keeping the inflammation low. So it is likely that decrease in these hormones causes an increase in levels of inflammatory cytokine, IL6 (Maggio et al., 2006, Abu-Taha et al., 2009). If these cytokines go up they will eventually lead to inflammation of tissues expressing them.

Is obesity just early ageing of adipose tissue?

Then, our metabolic profile also change as we age. I mean if you were paying attention the mitochondrial quality decline with age that we saw in last episode, it must have given it away. This effect may play an important role in how adipose tissue turnover in young vs old individuals. What we see in adipose tissue is that as we age, the adipose tissue not only redistributes but it also becomes pro-inflammatory. It accumulates a lot more macrophages. In fact when we look closer we can find a lot of adipose cells, pre-adipocytes and other cells of mesenchymal origin, display a senescent and pro-inflammatory state in old mice and men (Tchkonia et al., 2010). In fact, some researchers have proposed that obesity is a prematurely aged adipose tissue.

Summary

In a nutshell, what we saw in today's article is when we get old we get a low grade chronic inflammation in our body. We focused majorly on discussing what are potential sources of this inflammation. We found that both lifestyle and innate factors may contribute to age associated inflammation. While we covered a lot of it, there are other factors like chronic latent infections, such as with CMV, that you might want to check out. I also left out role of gut microbiome in inflammation and ageing . Also, what we did not talk today is role of phychological stress and stress hormones as we age. I will visit these topics in future, nevertheless. Anyhow, in the next episode, we will look into effect of caloric restriction on inflammation and take our quest further. In the meantime, you can focus on living a healthy lifestyle to minimize and delay the inevitable inflammation.

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References

The quest for elixir of life - understanding caloric restriction (episode 1 - DNA damage and repair)

The quest for elixir of life - understanding caloric restriction (episode 2 - mitochondria)

Type 2 Diabetes - from the eyes of immune cells.

The biology and physics of wound healing (part 1 - the cellular players and dynamics of healing)

Fibrosis-an overscarring wound

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