Reversing Ageing In Humans: What Might The Roadmap Look Like?

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No therapy has yet been developed that demonstrably reverses ageing in humans. Yet rejuvenation has been achieved many times in animal models, and prototype human treatments already exist and are under investigation. Optimistically and with the right effort and funding, we could see the first successful treatments targeting ageing in humans within the next few decades.

In this post on the FightAgeing! blog, Reason puts forward a list of 11 rejuvenation therapies and proposes the order in which they are likely to arrive in the clinic. Reason subscribes to the damage theory of ageing – that ageing is primarily driven by various types of damage that our cells and tissues accumulate throughout life, and that the most successful rejuvenation therapies will be those that can reverse this damage.

1: Clearing senescent ‘zombie’ cells

Our cells can only divide a certain number of times. Once this limit is reached, they enter a state called senescence. Senescent cells are supposed to destroy themselves or be cleared up by the immune system, but as we age their numbers start to build up and cause problems for surrounding tissues. There are compounds that will reverse senescence or selectively destroy senescent cells, and some of these drugs are known to be safe in humans as they are already used to treat other diseases. Whether they will actually reverse ageing in humans or extend our lifespan remains to be seen, but some clinical trials targeting specific age-related diseases are progressing and have shown promise.

2: Rejuvenating the gut microbiome

As we age, the population of bacteria that dwells in our gut becomes smaller and less diverse, with a loss of bacteria that produce beneficial molecules (like short-chain fatty acids) and a shift towards bacteria that promote inflammation. The gut microbiome seems to have a strong impact on many aspects of human health, and animal studies suggest that restoring it to a youthful state can prevent age related disease and slow ageing. Rejuvenating the human gut microbiome is actually very easy – a faecal transplant from a young donor achieves long-lasting rejuvenation of the gut microbiome, unlike probiotics, which do not survive in the human gut for long. Another approach is to vaccinate people against harmful strains of gut bacteria to help the immune system keep them at bay.

3: Clearing amyloid

Despite decades of research, the role of deposits of misfolded proteins known as amyloid in age-related diseases is still somewhat controversial. They’re likely to be playing some role, but may be a symptom of deeper issues rather than a primary cause of disease. Whatever the case may be, we’re probably going to need a way to remove amyloid deposits from our tissues, and some progress has been made towards this goal. Drugs that can remove amyloid from the brain have been developed but have mostly been disappointing when it comes to treating neurodegenerative diseases. It’s possible they would work better when used preventatively, but are currently too expensive/have too many side effects to justify this kind of usage.

4: A universal cancer cure

Cancer is an age-related disease that everyone can expect to get eventually if they live long enough. As already mentioned in the first entry, cells can only divide a limited number of times, so cancer cells must overcome this limit through mutations that extend their telomeres – sections of DNA at the ends of each chromosome that shorten each time a cell divides. 90% of cancers do this using an enzyme called telomerase. If telomerase could be blocked in cancer cells, most cancers would be easily treated. Once this works, we would only need to figure out how to prevent telomere extension in the remaining 10% of cancers that use alternative telomere-extending mechanisms. 

5: Restoring the thymus

The thymus is the organ in which new white blood cells are ‘trained’ to target pathogens and to ignore native human cells. With age, the thymus shrinks and dwindles to almost nothing, which obviously harms the function of the immune system, with knock-on effects on many other aspects of ageing (such as the removal of senescent cells). The ball now finally seems to be rolling when it comes to therapies designed to restore the thymus, applying a range of methods from gene therapy to the use of growth hormones.

6: Repairing damaged mitochondria

The mitochondria are the power plants that reside within our cells. Mitochondria have their own DNA, separate from human (nuclear) DNA, that encodes the proteins they need to function. This DNA is less protected from damage when compared to nuclear DNA. As a result, it accumulates damage with age, turning the mitochondria into dysfunctional factories producing harmful molecules thought to be major contributors to ageing. There are many approaches that could be used to fix this problem. On one end of the spectrum is mitochondrial transfusion – we can take young, healthy mitochondria and introduce them into ageing tissues. On the more extreme and futuristic end of the spectrum is genetic engineering – we could move the mitochondrial DNA into our nuclear DNA where it would be better protected and maintained. This would require us to genetically alter our own species, but this may be more achievable than it sounds. Most mitochondrial DNA has already been incorporated into the nuclear DNA naturally over the course of our evolution – we would merely be accelerating the completion of this process.

7: Restoring stem cells

Stem cells are cells that have not fully developed into a specific cell type. For example, stem cells in the bone marrow can give rise to many different types of white blood cell or to red blood cells. For them to continue to produce new fully developed cells throughout life, a pool of stem cells must be maintained, which means that stem cells need to be able to renew themselves. Unfortunately, this self-renewal capacity is lost in old age, which leading to the decline of many organs and tissues as they struggle to replace dead or damaged cells. This could potentially be fixed by introducing new healthy stem cells or therapies that rejuvenate existing ones. It’s a difficult problem to solve because each type of stem cell is its own unique case that requires its own solution.

8: Removing cross-links

With age, proteins can become joined together by other molecules, preventing them from functioning properly. Cross-links between neighbouring collagen and elastin molecules, for example, result in weakening and loss of elasticity in the skin and blood vessels. Because cross-linking occurs throughout the body and seems to universally involve a molecule called glucosepane, cross-linking is an exciting target, but unfortunately not much progress has been made.

9: Partial reprogramming

All our cells have the same DNA. What makes a muscle cell different from a brain cell are the modifications made to the DNA known as epigenetic modifications. Throughout life, a cell’s epigenetic identity can be altered, interfering with its ability to function. Research shows that an old cell’s epigenetic identity can be reset to a youthful state by exposing it to the correct levels of certain ‘reprogramming factors’. Remarkably, this seems to erase almost all signs of ageing. While exciting, this method comes with the risk of too much reprogramming erasing the cell’s identity entirely. Different tissues also require different levels of exposure to reprogramming factors, so putting partial reprogramming into practice is probably going to be a long and complicated endeavour.

10: Replacing the ageing immune system

As already mentioned, the decline of the immune system is an important component of the ageing process. One potential solution to this is simply to replace the immune system completely. Physicians already reconstruct a core component of the immune system when they perform bone marrow transplants, since this wipes out the cells that manufacture new white blood cells and replaces them. If we could wipe out the entire immune system (including its immune memory) and replace it with new healthy stem cells, we could in theory free up memory for new pathogens and cure autoimmune diseases by erasing memory of self antigens. A significant barrier to this is the side effects of chemotherapy required to destroy the immune system, but some drugs are in development that could target immune cells more specifically to avoid those side effects.

11: Cleaning up the rest of the garbage

As we age, various forms of ‘molecular garbage’ begin to accumulate within our cells and tissues. The previously mentioned amyloid is the most well known and researched form of garbage, but there are many others. These include molecules such as tau protein (which accumulates as filaments in various diseases including Alzheimer’s) and lipofuscin (lipid-containing granules that clog up our cells’ waste-disposal machinery). Therapies that can remove these unwanted waste molecules may eventually be developed, but since there are many different forms of waste (with no good information as to which ones are most impactful during ageing), research in this area might remain low-priority.

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So there you go, an interesting look at the order in which we might see the development of rejuvenation therapies. It’s also a nice list of some of the most promising treatments targeting ageing that are currently under development. As mentioned, you can find the original list with Reason’s commentary on the Fight Ageing! blog here.