Cellular aging: Improving health and lifespan
Each of us is used to the idea that as time moves forward, we will grow old. The world’s population has, in general, grown significantly older over the last century and while modern medicine has gotten much better at increasing lifespan, the problems associated with this increased longevity are becoming more and more apparent. Increased age is the biggest risk factor for almost all major diseases including cancer, heart disease and type 2 diabetes as well as neurodegenerative diseases like Alzheimer’s. So, while we may be living longer, the effects of time on our bodies has not been addressed with quite as much success. There is a rapidly growing field of research actively looking to address this point, however.
While it might sound unlikely, the ability to live forever is possible at the cellular level at least. We see the unfortunate fallout of this cellular immortality all too often in the guise of cancer. Cancer cells are for all intents and purposes immortal. They can, if given the right conditions in the lab, continue to grow indefinitely. We have evolved many systems to prevent the progression of cancer, and among those are mechanisms that actually limit how many times a given cell can divide. Serving as the countdown timer limiting cellular lifespan and capping the ends of our chromosomes are the telomeres. Telomeres serve several functions in our cells, but perhaps one of the most important arises due to a quirk in how our DNA copies itself. Known as the end-replication-problem, telomeres get a little shorter every time a cell replicates (which means we actually lose a little bit of DNA every time each one of our cells divide) and once they become short enough, they send out an emergency signal to the cell that forces the cell to “retire”. This cellular retirement is known as senescence and it’s becoming increasingly clear that aging as we know it and senescence are intricately linked.
Senescent cells are irreversibly forced out of the cell cycle, meaning they are no longer able to divide and replicate. While on one hand this is an important mechanism in stopping the progression of cancer, on the other, senescent cells can have a detrimental effect on the tissues and organs in which they are located. One of the defining characteristics of senescent cells is that they begin to release a whole host of pro-inflammatory signalling molecules known as cytokines, a phenomenon known as the senescence associated secretory phenotype or SASP. These cytokines can act locally on neighbouring cells or enter the blood stream and contribute to a body-wide, chronic, low-level inflammatory state known as “inflammaging”. In fact, the continuous inflammatory signals released by senescent cells are now believed to be a very significant driver of aging. Many of the inflammatory cytokines released by SASP are known to be a direct cause of some of the most impactful physical changes we see in the elderly. Interleukin-6 and tumour necrosis factor α (known as IL-6 and TNF-α) for example have been shown to be major promoters of muscle loss. Interestingly, SASP is also capable triggering nearby cells into becoming senescent, a phenomenon known as the bystander effect. This means the appearance of one senescent cell is capable of pushing neighbouring cells to enter senescence early, compounding the problem.
Several important studies from the lab of Jan Van Deursen, (See Review 1), using genetically altered mice showed how important the process of senescence is in ageing by removing senescent cells in ageing animals. In their mouse model, senescent cells gained the ability to metabolise a non-toxic pro-drug to a toxic drug, resulting in those cells being killed. Meanwhile, non-senescent cells were left incapable of this metabolic process and stayed healthy and unharmed. This system effectively allowed the researchers to specifically target and kill senescent cells within mice that were allowed to age naturally. Their results clearly showed an increase in both lifespan and healthspan (how long the mice were fit and healthy for) proving that just by removing senescent cells and preventing their negative influence, some of the major signs and symptoms of ageing could be prevented. Building on these studies other researchers have used the same system to demonstrate that removal of senescent cells leads to an increase in bone strength, improved regenerative capacity of heart muscle and overall cardiovascular function, improved metabolic function and even improved cognitive function in a mouse model of Alzheimer’s disease.
The clear success of this approach in mice, while encouraging, is not directly translatable to humans unfortunately. All of these studies have been carried out using a genetically modified mouse model, as mentioned above, capable of metabolising a pro-drug to a toxic metabolite. Since we are a long way from reliable and safe gene modification therapies in humans, this approach is not yet clinically relevant. It has, however, provided significant understanding and know-how for a quickly expanding field examining senolysis. As the name implies (seno- from senescent and lysis- the latin to destroy or breakdown), senolytic therapy is focussed on finding drugs that can specifically target and remove senescent cells. Several promising molecules have been discovered and are currently undergoing evaluation. A study examining a combination therapy consisting of quercetin and dasatinib published last year in The Lancet, for example, has been shown to reduce the level of senescent cells in tissues in a human trial. This trial showed that in patients with idiopathic pulmonary fibrosis, a lung disease in which the accumulation of senescent cells is thought to play an essential role, senolytic therapy significantly improved lung function.
Senescence is an important aspect of ageing, showing how changes at the cellular level contribute to whole body ageing, but it is important to remember that it is still only one contributing factor. Another topic which has received particular attention in the media in recent years is the idea of supplementation to increase cellular NAD+ levels. NAD+ (nicotinamide adenine dinucleotide) is a crucial coenzyme in the production of ATP. ATP can be thought of as the energy currency in our cells, meaning that without NAD+ we cannot convert our food into useable energy and all processes within our cells grind to a halt. It’s estimated that over the average lifespan NAD+ levels decrease by half, meaning as we age our metabolism becomes less efficient and all of the many cellular processes that require NAD+ are also negatively affected.
The role of NAD+ decline in ageing goes beyond regulating metabolic function. NAD+ is also essential for many crucial cellular processes with direct consequences for aging. Enzymes involved in DNA damage repair (PARP1), gene expression and mitochondrial function (the sirtuins) and many other vital cellular functions rely on NAD+ to carry out their roles. The sirtuins in particular have received a lot of attention as potential targets for slowing down or reversing the effects of age. Sirtuins as a family of proteins are NAD+ dependant deacetylases whose function is to remove acetyl groups from other proteins within the cell. Generally, acetylation has an inhibitory effect on the function of most proteins so removal of acetyl groups by sirtuins in the presence of NAD+ results in activation of many cellular functions. For example, referring back to PARP1 involved in DNA damage repair could be directly affected by a reduction in NAD+ levels resulting in a decreased ability to respond to DNA damage.
At the cellular level, ageing is a particularly complicated network of interacting driving factors. It is exactly this complexity that has prevented us developing a more concrete understanding of “ageing” as a whole. We are only now at a point where we are beginning to understand how individual contributors like senescence or age-related NAD+ decline might drive ageing and it’s becoming clear how complicated ageing as a disease truly is. There is likely a high degree of cross-talk between contributing pathways, for example senescence can drive metabolic dysregulation and reduce NAD+ levels. Conversely, reduced NAD+ levels can cause senescence by inhibiting proteins involved in DNA damage repair leading to accumulation of critical levels of DNA damage. We might not yet be in a position to tackle the cause of some of these drivers of ageing, but now that we know their downstream effects we might at least be in a position to try to treat them at that level
Here at Nuritas, this is the approach we have decided to take. Using our proprietary artificial intelligence platform, NπΦ, we have identified several naturally occurring peptides that can be enzymatically released from the Leguminosae (pea) family of plants. The resulting purified peptide matrix named PeptiStrong, was initially conceived and designed to promote muscle recovery and maintenance. While undergoing extensive characterisation to verify the molecular mechanisms that PeptiStrong modulates, it was shown that TNF-α signalling was significantly suppressed by PeptiStrong treatment. TNF-α plays an essential role muscle loss (it was originally referred to as atrophin) and so suppression of the TNF-a pathway by PeptiStrong helps to prevent muscle loss. TNF-α is also a major component of the SASP cytokine mixture released by senescent cells and in fact it is now believed to be the major cytokine involved in pushing non-senescent cells into becoming senescent cells, the bystander effect mentioned above. PeptiStrong might therefore have beneficial effects in combatting the progression of ageing by acting on several fronts. First and foremost, by preventing muscle loss PeptiStrong should help maintain physical strength and agility (preventing falls, helping to maintain physical activity and promoting normal metabolic activity). Secondly by helping to suppress the pro-inflammatory effects of SASP, PeptiStrong might help to at least alleviate the chronic inflammation, or inflammaging, that seems to be at the root cause of many of the diseases we associate with ageing.
By understanding the events that lead to whole-body aging from a cellular level, we are now more than ever in a position to begin to design interventions that might be helpful in slowing the ageing process to allow our progress in extending healthspan to catch up to the already impressive progress that has been made in extending lifespan.
- Van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509(7501):439-446. doi:10.1038/nature13193
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 894001