We have been busy advocating for rejuvenation biotechnology. Elena Milova recently attended the first International Longevity and Cryopreservation Summit in Madrid with a talk about how to deliver the most effective messages to engage the general public to support aging and rejuvenation research.

We will shortly have a number of exciting articles about the conference, including exclusive interviews, but while we prepare them, we have rushed this very exciting news to you.

Elena had the opportunity to talk with Dr. Aubrey de Grey from the SENS Research Foundation at the conference, and she asked him one of the most important questions about SENS: where are we now? Here is what Aubrey had to say about this question.

The SENS Research Foundation has divided aging damage into seven broad categories, each with a solution in order to treat or prevent age-related diseases. We have summarized all of these aging damages below as well as the current state of progress for each.







It is important to note that while SENS is slightly different from the Hallmarks of Aging, which we normally talk about at LEAF, they are essentially similar, as they both promote a damage repair approach. Indeed, we consider these approaches to be compatible in their aims, and thus we support them both.

RepleniSENS: Cell loss and tissue atrophy

Over time, our cells are damaged from various sources, including trauma, environmental exposure to toxins, oxidative stress and other stressors. Sometimes, the damaged cells are repaired, but sometimes they are destroyed, become dysfunctional and cease dividing (senescence), or are so damaged that they destroy themselves (apoptosis) to protect the body.

Some of these lost cells have to be replaced by pools of tissue-specific specialized stem cells, but, over time, these reserves run low, leading to increasingly less effective repair.

Over the course of decades, long-lived tissues – such as the brain, the heart, and skeletal muscles – gradually lose cells, and as replacement dwindles, their function becomes compromised. This leads to loss of muscle strength, poor injury recovery, and muscle wastage known as sarcopenia – one of the reasons why older people are frail.







The brain also loses neurons, which leads to cognitive decline and dementia as well as the loss of fine muscle movements and, ultimately, Parkinson’s disease. The immune system also suffers, with the thymus gradually shrinking and losing the ability to produce immune cells, leaving you vulnerable to diseases.

Where are we now?

Thankfully, this is already a well-advanced field. SENS has not needed to get involved in this area, as it is well funded and moving along very rapidly. Only this month we have seen hematopoietic stem cells produced for the first time, and research in this field is moving forward at a furious rate.

It is plausible that, in the near future, we will be able to produce every cell type within the body to replace age-related losses. This will allow us to replenish the immune system, repair the damage caused by neurodegenerative diseases such as Alzheimer’s and Parkinson’s, and repair organs.

OncoSENS: Cancerous cells







Two types of damage accumulate in our genes as we age: mutations and epimutations. Mutations are the result of direct damage to the DNA itself, and epimutations are damages to the scaffolding of DNA that controls gene expression somewhat like a lens. Both forms of damage lead to abnormal gene expression, which causes the cell to malfunction. The most common form of cell malfunction is uncontrolled growth, better known as cancer.

Cancer can use two different pathways to grow: hijacking telomerase and the Alternative Lengthening of Telomeres (ALT) mechanism. Both allow cancer to maintain its telomeres, thus remaining immortal and growing out of control. Therapies that can inhibit these pathways could be combined and are therefore a potential way for us to defeat all cancers.

Where are we now?

ALT therapies are progressing following a successful fundraiser on Lifespan.io last year, which raised an amazing 72k. SENS has been developing a high-throughput assay for ALT, allowing cost-effective candidate evaluation for drugs that can inhibit or destroy cancer cells using ALT. Within the next year, a company based on ALT should be possible.

Telomerase-inhibiting therapies are being developed by a number of organizations and companies, so the SENS Research Foundation does not need to get involved with this. Therapies that inhibit telomerase in cancer cells are already in clinical trials and are well funded.







MitoSENS: Mitochondrial mutations

The mitochondria are the power plants of the cell, converting nutrients from food into energy known as ATP, a form of energy that powers cellular function. Unlike the rest of the cell, mitochondria have their own DNA, known as mtDNA, which is outside of the cell nucleus where the rest of our genes are kept.

The problem is, as mitochondria produce ATP, they also generate waste byproducts; in this case, they are highly reactive molecules called free radicals. Free radicals can strike and damage parts of the cell, including mtDNA, which, due to its close proximity to the source of free radicals, is very vulnerable to these damaging strikes.

A strike can delete sections of mtDNA, leaving the mitochondria unable to produce ATP. Even worse, these damaged mutant mitochondria enter an abnormal metabolic state to remain alive. This state produces little energy and generates large amounts of waste that the cell cannot dispose of.

Ironically, the cell even preserves these damaged mitochondria instead of disposing of them and sends healthy ones to be recycled instead; this means that mutant mitochondria and their progeny can rapidly take over an entire cell. This leads to cells with damaged mitochondria that dump waste into the circulatory system, causing system-wide levels of oxidative stress to rise and driving an aging process.







The solution to this problem is to move the mtDNA to the cellular nucleus, where it will have a far greater level of protection from free radical strikes. Indeed, evolution has already started doing this in our cells and has already moved around 1000 mitochondrial genes to the nucleus. SENS Research Foundation is proposing to accelerate the process that nature has started.

Where are we now?

The SENS Research Foundation successfully fundraised for the MitoSENS project on Lifespan.io back in 2015. It then followed up with a publication in the prestigious Nucleic Acids Research journal, showing its results in September 2016.

Thanks to the support of the community, the MitoSENS project succeeded in migrating not one but two mitochondrial genes to the cell nucleus, a world first. Since then, progress has been rapid, and the researchers have now almost migrated 4 of the 13 mitochondrial genes. They are currently refining the process into a standardized therapy.

ApoptoSENS: Death-resistant cells







Our cells have a built-in safety mechanism known as apoptosis, allowing them to destroy themselves when they are damaged or dysfunctional and eventually be disposed of by the immune system. However, as we age, cells increasingly fail to dispose of themselves in this manner, and they enter a state known as senescence.

Senescent cells do not replicate or support the tissues of which they are part; instead, they send out pro-inflammatory signals that poison their healthy neighbors, causing them to also become senescent.

The same pro-inflammatory signals block stem cell activity and prevent them from repairing tissue. As we age, more of these cells build up, leading to increasingly poor tissue repair and regeneration. The solution to this problem is to remove senescent cells periodically in order to help maintain tissue repair and maintenance. Therapies that remove senescent cells are known as senolytics and have been big news for the last year or so.

Where are we now?

There has been a huge level of interest in senescent cell removal therapies in the last year or two, and a number of companies are currently developing senolytics. Unity Biotechnology is taking the first generation of senolytics into human clinical trials this year, after being successfully funded by Amazon’s Jeff Bezos and a number of other big investors.







However, the heat is on as other companies are following up close behind, with potentially more sophisticated approaches for removing senescent cells, such as plasmid-based solutions from Oisin Biotechnologies and a synthetic biology approach from CellAge, which successfully fundraised on Lifespan.io last year.

The SENS Research Foundation is also working on a joint project with the Buck Institute for Research on Aging on senescent cells this year, with particular focus on senescent cells in the immune system.

GlycoSENS: Extracellular matrix stiffening

Much of the structural features of the body are made of proteins that are created early in life. These structures are either not replaced or recycled, or if they are, this occurs at a very slow rate over decades. These structural components are made of proteins, and their health relies on their proteins maintaining their own structure.

These proteins are responsible for the elasticity of tissue, such as in the skin and blood vessel walls as well as the transparency of the lens of the eye. Unfortunately, blood sugar and other molecules react with these structural proteins and bond with them, creating fused crosslinks.







Crosslinks bind neighboring proteins together, impairing their movement and function. In the case of the arterial wall, crosslinked collagen prevents the artery from flexing in time with the pulse, leading to hypertension and a rise of blood pressure.

This loss of flexibility increases over time, meaning that the full force of blood being pumped around the body goes directly into the organs, damaging them, instead of being absorbed by the blood vessel walls. In time, this leads to organ damage and an increase in the risk of stroke.

The SENS Research Foundation proposes to find ways to break down these crosslinks in order to restore movement to the structural proteins and thus reverse the consequences of their formation. There are multiple types of crosslinks that accumulate in the body, but the focus is on glucosepane, which is a very long-lasting crosslink that the body can only break down very slowly if at all.

Where are we now?

The problem for many years was obtaining enough glucosepane to be able to test therapies on. Thanks to funding from the SENS Research Foundation, progress at Yale University now allows the cheap production of glucosepane on demand, which means that researchers can now test it directly and find antibodies and enzymes to dissolve the accumulated crosslinks.







Yale already has some antibodies against glucosepane; it is anticipated that, by the end of the year, monoclonal antibodies will be available, and there is strong evidence for bacteria with enzymes that can break glucosepane.

AmyloSENS: Extracellular aggregates

Misfolded proteins produced in the cell are normally broken down and recycled within the cell. However, as we age, more and more misfolded proteins accumulate, forming sticky aggregates. These misshapen proteins cannot function normally, and they impair cell or tissue function with their presence.

This extracellular junk is known as amyloid, and it comes in a number of types. Amyloids contribute to Alzheimer’s, Parkinson’s, ALS, and other, similar diseases in the brain as well as to islet amyloids in type 2 diabetes and senile cardiac amyloidosis.

One solution is to remove these aggregates from the brain and other areas of the body by using specialized antibodies that target them and remove them from the tissue. This could help to prevent or reverse amyloid-based diseases.







Where are we now?

The work that SENS Research Foundation funded at UT Houston in Sudhir Paul’s lab is now in the hands of his company, Covalent Biosciences. Hopefully we will hear some news from this company in the near future.

Fortunately, a number of alternatives are in development, such as the GAIM system, which has been funded by the Michael J. Fox Foundation and appears capable of clearing multiple types of amyloids, included those associated with Alzheimer’s, Parkinson’s, and amyloidosis. The AdPROM protein targeting system also holds promise for selectively degrading target amyloids and other undruggable proteins to treat age-related diseases.

LysoSENS: Intracellular aggregates

In time, the proteins and other components of our cells become damaged through the wear and tear of normal metabolism. Cells have a number of systems for breaking down unwanted materials; the lysosome is one of them. The lysosome can be considered to be a kind of cellular garbage disposal unit that contains powerful enzymes for breaking down unwanted materials.







However, sometimes materials are fused together so well that not even the lysosome can break them down. This leaves the unwanted material sitting there, and, over time, more and more of this material accumulates until it starts to interfere with the lysosome’s function. This is a problem for cells that have to last for a lifetime, such as heart and nerve cells, and as more and more of these cells become dysfunctional due to the lysosome malfunctioning, age-related diseases are the result.

For example, in heart disease, macrophages are responsible for clearing away the toxic byproducts of cholesterol in order to protect our arteries. Macrophages swallow these toxic materials and send them to the lysosome for disposal and recycling.

However, over time, their lysosomes become engorged with toxic materials that they cannot break down, which eventually kills them or immobilizes them, leaving them embedded and dysfunctional in the arterial wall. In time, the numbers of these dysfunctional macrophages increase and form the plaques associated with atherosclerosis. Ultimately, the plaques build up, and the injury swells and eventually bursts, causing blood clots that trigger heart attacks and strokes.

The solution that the SENS Research Foundation has proposed is to identify new enzymes that can digest these insoluble wastes and then supply macrophages and other cells with these enzymes in order to break these wastes down.

Where are we now?







Ichor Therapeutics is taking SENS Research Foundation-based technology to market for macular degeneration with a therapy that removes a Vitamin A derivative that accumulates in the eye and causes blindness. Ichor has successfully conducted a seed round and is now doing a $15 million Series A round. The company is less than a year away from human clinical trials.

Conclusion

There is much to be optimistic about. The ideas proposed by SENS over a decade ago, widely criticized in the past, are now being eagerly explored by researchers as it becomes ever more apparent that the aging processes are amenable to intervention. What was mocked just over a decade ago is now becoming an accepted approach to treating age-related diseases, as the results continue to mount up in support of a repair-based approach to aging.

However, we still require more knowledge about several age-related damages in order to progress to clinical trials in humans. This is why supporting fundamental studies on the main mechanisms of aging should remain the number one priority for our community.

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