GeroScience is a scientific journal leading the charge in the biological study of ageing and chronic age-related diseases. GeroScientists conceptualize biological ageing into 7 pillars, that are separate but interconnected.
Ageing is a multi-dimensional process, meaning that one pillar can affect another or many pillars; these effects can compound over time, often exacerbating ageing systematically across all pillars.
The connectedness between the pillars was described by researchers as ‘striking’, because, these seven pillars are…
“not seven independent factors driving aging; rather, they were highly intertwined processes, and understanding the interplay between these seven pillars is critical”.Optimal functionality requires overall health, thus, there is a great need to understand the systemic relationships of ageing, to develop best practices that work across all seven pillars of ageing to mitigate the detrimental biological effects of ageing.
If the COVID-19 pandemic has proven anything, it is the extent to which health vulnerable persons tend to not only have one underlying health condition but have multiple underlying health conditions – exacerbating morbidity. Thus, targeting diseases individually is often ineffective because the presence of multiple health conditions interact and have a confounding effect on therapeutic strategies.
E.g. once one thing goes wrong, everything else starts to go wrong.
The connectedness between the ageing pillars will enable new therapeutics to arise that will work for multiple chronic diseases by targeting ageing directly at the network level.
Macromolecular Damage can be understood as the deterioration of the building block cells of the body. These cells are known as macromolecules: DNA, lipids, proteins (amino acids), and carbohydrates (polysaccharides). As we age, these macromolecules deteriorate and accumulate in and around our cells.
Proteins involved with visual aesthetics such as skin, hair, and muscle tone, will over time deteriorate – wrinkles are a classic sign of ageing. This deterioration is the protein not forming correctly and is characterized by the protein misfolding, oxidizing, or when glycation goes array, creating advanced glycation end-products. This is when sugar molecules incorrectly attach to a protein or other macromolecule. Over time these junk proteins build up and start to take up space, and interfere with our body’s ability to effectively clear these damaged cells from our body – a process known as autophagy. imagine you are in a room, and there’s a thousand bits of paper on the floor and one bin in the corner. You are tasked to pick up one bit of paper, take it to the bin and dispose of it. However, every minute, one person enters the room and this continues until the room is saturated with people – all getting in your way. How difficult is it for you then to make your way around the room, pick up each piece of paper, and then dispose of it. Over time it becomes near impossible. This is akin to how the body struggles as it ages to remove junk proteins. The accumulation of junk proteins then exacerbates other ageing factors.
The epigenome consists of chemical compounds that can tell the genome what to do. The genome – your DNA – is the blueprint for how your cells are put together and how they should function. The epigenome sits alongside your genome and can turn genes on or off. The epigenome does not alter your DNA blueprint – that is fixed – but it alters how your cells interpret the DNA’s instructions.
For example, a captain sailing a ship acts like an epigenome. The ship, it’s the crew and the charted root is the DNA blueprint – the fixed factors. The captain can sense and interpret the environment and respond by giving orders – turning genes on or off – to adjust certain factors with the ship, such as the deck numbers, sail configurations, and heading to complete the voyage.
As we age, our cells are continually put under stress from the environment and this changes the body’s epigenome; this environmental stress can change your epigenome both positively and negatively. The negative changes are what result and exacerbate ageing, and are often triggered by environmental toxins, chemicals, drugs, pharmaceuticals, infectious diseases, and lifestyle factors. These stressors cause changes in the epigenome which then alter signals that interfere with DNA methylation, RNA, and histone. Over time these changes start to impact the other pillars of ageing and increase the likelihood of diseases like diabetes and cancer occurring.
Inflammation in regards to ageing refers to body-wide low-level chronic inflammation. The exact ways in which inflammation is a causal or contributing role in ageing is still unknown, however, it can be said with certainty that all age-related diseases – think, diabetes, heart disease, cancer, and dementia – are strongly associated with body-wide low-level chronic inflammation – technically known as inflammatory pathogenesis.
Inflammation is not a bad thing in and of itself; in fact, many of the health benefits we get from exercise are as a result of the inflammatory response. Similarly, the way we build a strong immune system is by exposure to pathogens, followed by an inflammatory response by your immune system. For example, a doctor, if they suspect infection or disease will likely test for inflammation. They will test for the elevation in serum levels of several cytokines and acute phase factors. Three of the most commonly tested for are: C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α).
As we age, this inflammatory response by your immune system can become dysfunctional, and instead of turning off after pathogen exposure, can remain on, meaning your body remains in a constant stressed state. This overactive immune system state accelerates ageing throughout the body, impacts the other pillars of ageing, and can result in the onset of age-related diseases.
This pillar of ageing refers to how we adapt to stress both at a psychological and molecular level and recognizes the influencing inter-connection between psychological stress and molecular stress. For example, psychological stress can lead to the release of cortisol in the body – a molecular response – which if chronic can exacerbate ageing. The influence also works in reverse; for example, if you are exposed to environmental toxins, the molecular response can cause a psychological response, which can then become a vicious cycle of compounding psychological and physical stress.
However, not all stress is bad; it is important to differentiate between toxic stress and hormesis. If the stress is of an optimal level for you to recover from, the stress or toxin can have a positive effect on your physiology and psychology, which extend the life and slow the effects of ageing.
People’s adaptive stress levels are what differentiate one’s anti-ageing potential. For example, some people can naturally train physically a lot, just as some people can take on a lot of psychological stress and still function – they have a higher hormetic zone for certain stress. Whereas others can’t function at similar or lower stress levels. This variation affects whether the stress effect becomes chronic or acute. Chronic being the worst for ageing-related effects and diseases.
Proteostasis is the process that oversees the regulation and maintenance of all proteins in the human body – also known as the proteome. Proteins in the body are not just essential to building muscles and skin, proteins are utilized in many life-sustaining processes throughout the body. Pretty much all cellular activity requires proteins at one point. Proteins firstly need to be assembled correctly so that they work, and secondly, they have a shelf life, and once expired they need to be removed before they become junk and cause havoc.
Proteostasis is the quality control mechanism that oversees the body’s protein lifecycle. The technical names for some of these quality control mechanisms are chaperones, autophagy, proteasomal degradations, endoplasmic reticulum (ER), and mitochondrial unfolded protein responses (UPRs).
However, sometimes these mechanisms go array the proteins get assembled incorrectly – misfolded. Misfolded proteins become junk cells and will often clump together with other damaged cells. This accumulation of junks cells accelerates ageing; the term garb-aging has been coined to describe it, which is the combination of garbage and aging. Garb-aging interferes with correct cell function and also triggers chronic inflammation, which was discussed in an earlier section.
Ageing presents two challenges to proteostasis: the first, is body’s quality control mechanisms worsen with age and therefore garb-aging increases with age; the second, is garb-aging exponentiates garb-aging, thus, your body as you age needs to deal with more and more junk cells, all while the body’s quality control mechanisms are a decrease in effectiveness over time.
Using Alzheimer’s disease as an example, the loss in the effectiveness of autophagy (cellar cleaning) leads to garb-aging in the brain. Amyloid plaques are junk cells, strongly associated with Alzheimer’s disease that build-up due to poor autophagy in the brain.
Of all the anti-ageing and next-generation medical treatments, stem cells have to be the most widely known and purported of the last twenty years. At times being touted as a potential cure-all and at other times being demonised as an immoral baby-killing procedure. Despite this, stem cells have over the last few years, with the help of Joe Rogan, become popular as a means to recover from injury and bring function and vigour back to ageing persons.
Their specific role in ageing is recognized, but it is not fully understood. Their role in ageing is not quite as straightforward as first thought. The role of stem cells in ageing depends a lot on the specific area of the body, for example, with muscles, stem cells are present even in the advanced years of ageing, so this says it is not a declining number of stem cells which is causing ageing. Instead, something is going on in the local tissue environment that means present stem cells are not being activated. This is why the effectiveness of injecting stem cells as a strategy to heal and regenerate tissue has not been as effective as first thought – the local tissue environment is not responding by activating the stem cells.
So what is it about the local tissue environment of younger people that activates the stem cells? It appears to be some specific component – special blood factor – in the blood that is present in younger people but not in older people. Over the last few decades, a series of parabiosis experiments (which is where they inject the blood of young mice into older mice and vice versa and observe tissue changes) have taken place to try to locate this special blood factor, but have so far been unsuccessful.
Currently, scientists are in a race to find out what this special blood factor is because if they can locate it as a specific compound this changes the anti-ageing and regenerative health game when it comes to stem cells.
It is quite a well-known trope with those over thirty that the metabolism slows as it ages. It is not uncommon to look back on teenage years and early twenties and reminisce at the amount of sh*t food you could eat and not get fat… whereas after thirty, a moment on the lips becomes a lifetime on the hips.
The metabolism slows as we age because of deregulated nutrient sensing. In more common parlance this means our cells don’t respond to/partition nutrients as effectively as they once did. The slowing of the metabolism not only makes one more prone to weight gain and muscle loss (higher levels of lean body mass is a strong indicator of longevity), it also means the body becomes more susceptible to chronic diseases, which then exacerbates the other pillars of ageing. Some of the most common age-related diseases are metabolic diseases, such as a variety of cancers, cardiovascular disease, type-2 diabetes, and neurodegenerative diseases.
Our cells need the energy to function and that energy is delivered into the cells through different nutrient-sensing pathways with the assistance of enzymes that will up and down-regulated in number depending on the energy demands and fuel sources available. Some of the most important nutrient-sensing pathways are:
- Insulin and IGF-1 signaling pathway (IIS): glucose-sensing
- mTOR: senses high amino acid concentrations
- AMPK: senses low energy states by detecting high AMP levels
- Sirtuins: senses low energy states by detecting high NAD+ levels
- Coenzyme Q10: essential for generating cellular energy.
- Cardiolipin: optimizes the function of numerous enzymes that are involved in cell energy production.
- Carnitine: Transports fatty acids into cells to be oxidized for energy production, and also participates in removing waste products from cells.
Imagine how hard it is to perform well in a running race when you are undernourished; this is the state of your cells when they lack these three key nutrients. And as we have seen with many of the other pillars of ageing, stress creates stress, which exacerbates the other pillars of ageing. There is also evidence that metabolic changes impact the micro-biome and the body’s circadian rhythm which can trigger metabolic irregularities and pro-inflammatory effects. Closing Thoughts… Ageing isn’t all bad news; yes, we are facing a demographic time-bomb that could lead to some dire economic and societal impacts (we might already be there with COVID-19), and yes, modern medicine is incredible at decreasing morbidity, but fails to prevent or reverse the decline in healthy life expectancy years – it can keep you alive but are you ALIVE? These issues are starting to be felt and this will hopefully lead to increased funding and research; therefore, the future is optimistic for anti-ageing therapies. We are not that far off – currently, ageing can be delayed with genetic, dietary, and pharmacologic approaches; which will be discussed in the next blog post in this series. So stay tuned and make sure to check back, because I may just show you what tools, supplements, and procedures you can use to create your very own fountain of youth.
Written by Let’s Eat Meat