Posted on 14 June 2021
In this series of articles, we discuss the nine ‘common denominators’ of the ageing process – the hallmarks of ageing. What exactly they are, how they change during ageing, and how we might be able reverse them in the future? Hopefully, by the end of this series, you will have a wider understanding of what actually makes us age.
The cells that make up our bodies do not exist and behave in isolation from one another – far from it: cells are constantly exposed to a huge and diverse range of external signals, some originating from neighbouring cells, others carried by the blood from distant tissues, and some taking the form of electrical signals. Cells of our bodies can also be influenced by signals originating from the bacteria in our guts. This signalling between cells is called intercellular communication, a kind of biological telecoms network which forms the basis for the coordination of various physiological functions within a multicellular organism. This signalling network is extremely complex, meaning that small changes in one system can have significant and often unpredictable effects in other systems. It is because of intercellular signalling that studying cells within living organisms is usually more relevant to human health than studying them in a dish, as cells in culture may behave very differently when deprived of their signalling environment.
Without intercellular communication, tissues would not be able to coordinate the necessary number, distribution and localisation of different cell types, as each cell would have no means of ‘knowing’ the location and status of its neighbours. Intercellular communication is necessary in order to coordinate an appropriate immune response to a threat, allowing the immune system to walk the fine between eliminating a pathogen and causing serious damage to the body’s own tissues. Intercellular communication also allows for the control of metabolic processes throughout the body. As covered in altered nutrient sensing, insulin and glucagon released by pancreatic beta cells regulate energy metabolism and cell growth throughout the body.
One of the most prominent and important changes in intercellular signalling that occurs with age is an increase in continuous ‘background’ inflammatory signalling. Inflammation plays a role in almost all chronic diseases of ageing including atherosclerosis, cancer, neurodegenerative diseases and diabetes. It is therefore not hard to see why an increase in inflammatory signalling is considered to be a hallmark of the ageing process.
Inflammation is an important process that works in tandem with our immune system to protect us against foreign invaders. Inflammation occurs in response to molecules the body doesn’t recognise, and in response to damage. It helps white blood cells gain access to our tissues, supports their function, and impedes the progress of pathogens. However, inflammation also damages our tissues, and must therefore be tightly controlled. A variety of molecules called inflammatory mediators, produced mainly by white cells but also by regular cells, are responsible for stimulating the inflammatory response. Even in young, healthy individuals, low levels of these inflammatory signals can be found in the blood, but this background inflammation increases with age. This increase is often referred to as ‘inflammageing’.
There are many causes for this increased inflammatory signalling, each of which can be traced back to other hallmarks of ageing. The rise in tissue damage caused by factors such as mitochondrial dysfunction triggers the release of inflammatory mediators. Accumulating senescent cells produce inflammatory mediators as discussed in cellular senescence. In the bone marrow, haematopoietic stem cells experience a shift in their ability to differentiate and begin to produce more white cells that are associated with inflammation. This causes the immune system to drift towards a more inflammatory state. Epigenetic changes can increase the activity of pro-inflammatory genes (epigenetic alterations), while misfolded proteins can act as a danger signal that triggers inflammation (loss of proteostasis).
Beyond inflammation, intercellular signalling may act as a kind of link between the ageing status of cells throughout the body. For example, we mentioned in the previous article (stem cell exhaustion), that transplantation of young stem cells into older organisms could improve tissue function even in tissues that received no stem cells. Transfer of blood from young mice to older mice also has rejuvenating effects, suggesting that factors released by cells and circulating in the blood (be they beneficial or deleterious) influence the ageing process across tissues.
Given the importance of inflammageing, the activity of inflammatory pathways is a key metric for gauging intercellular communication. One key player in inflammageing seems to be the inflammasome – a complex system of proteins that assemble together inside cells in response to stress, triggering the release of inflammatory signals. Activity of inflammasome proteins within a sample of cells can be measured relatively easily using immunostaining techniques (antibodies are used to target and detect the proteins of interest), as can the levels of inflammatory mediators in the blood.
Efforts have been made to measure the changing levels of thousands of proteins found in the blood throughout life. However, we have only really scratched the surface in terms of understanding which of these proteins constitute important signals related to ageing. Aside from proteins, another form of intercellular signalling that has gathered interest is via RNA molecules released freely from cells or carried in membrane packages called extracellular vesicles. This extracellular RNA (exRNA), once thought to be junk, can actually be taken up by cells and affect the proteins they produce. exRNA signals have been found to change with age, and this may be an important component of altered intercellular communication.
There are a number of strategies that could potentially be used to modulate intercellular communication to influence the ageing process. Several companies are currently researching and conducting clinical trials for rejuvenation strategies based on the use of blood-borne systemic factors. As touched upon earlier, transfusion of blood from young mice to old mice has rejuvenating effects, probably due to a combination of the introduction of beneficial factors from the young organism, and the dilution of harmful factors already circulating. Here is an article in which you can find out more about this approach, as well as a list of clinical trials being conducted.
There is evidence that organisms engineered to experience less inflammageing (such as mice lacking the inflammasome) exhibit less cognitive and physical decline. Any number of genetic, nutritional or pharmacological interventions that address inflammation directly or indirectly (through modulation of oxidative stress and other sources of damage) have the potential to slow the ageing process. For example, dietary restriction, anti-oxidants and long-term administration of anti inflammatory drugs like aspirin have been shown to extend lifespan in animal models. Unfortunately, due to the difficulties of studying lifespan extension in humans, it is uncertain whether any of these actually impact human lifespan. If they do, the benefits are certainly far less pronounced than they are in animals.
In our efforts to correct intercellular communication in old age, we should not forget the most numerous cells in our bodies – the bacteria in our guts. The gut microbiota is now recognised to play a profound role in our health, signalling to both our immune cells and our nervous systems. With age, the gut microbiota deteriorates in various ways, becoming less diverse and increasingly populated by bacteria that produce harmful signals. Reversing these changes, for example through probiotics or dietary interventions, may prove highly beneficial.
The Hallmarks of Aging: https://dx.doi.org/10.1016%2Fj.cell.2013.05.039
Basics of Cell Signaling: https://application.wiley-vch.de/books/sample/3527333665_c01.pdf
Undulating changes in human plasma proteome profiles across the lifespan: https://dx.doi.org/10.1038%2Fs41591-019-0673-2
Extracellular RNA in Aging: https://dx.doi.org/10.1002%2Fwrna.1385
NLRP3 inflammasome suppression improves longevity and prevents cardiac aging in male mice: https://dx.doi.org/10.1111%2Facel.13050
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