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The SENS Research Foundation on the Ongoing Development of Senolytic Therapies to Treat Neurodegenerative Conditions

Senescent cells are a significant cause of age-related disease. Now that the research community is earnestly developing ways to remove senescent cells, and trying them out in animal studies, every few months there is a new announcement of one or another definitive connection between the accumulation of senescent cells and a specific medical condition. The SENS vision for the development of rejuvenation therapies assembled the existing evidence and strongly advocated for senescent cell clearance around the turn of the century, ten long years prior to the point at which the rest of the research community finally got on board. In a better world, most of the impressive progress today towards the effective treatment of many age-related diseases by clearance of senescent cells would have happened certainly ten and perhaps twenty years ago. There is no compelling technical reason for it to have waited until now; the delay is near all cultural, a consequence of the attitudes of the research community during the decades in which its members actively discouraged work on slowing or reversing the aging process.

It was a bit of a mystery to the scientists investigating the phenomenon: a brain disease driven by the death of specialized neurons was strongly linked to exposure to a particular pesticide. Why, then, didn't exposing those same neurons directly to that same pesticide seem to affect them? Parkinson's disease (PD) is a neurodegenerative disease of aging, whose most obvious symptoms involve the loss of fine motion control. This is the result of the loss of specialized cells in an area of the brain called the substantia nigra pars compacta (SNc) that specialize in producing the chemical signal-molecule dopamine. Once a critical number of these dopaminergic SNc neurons are lost, the unbalanced firing of those neurons begins to manifest itself in the main motion-related symptoms of the disease.

In all but a few people with rare mutations, degenerative aging processes (such as the accumulation of mitochondrial mutations in SNc neurons) are primarily responsible for the disease. But lifestyle and environmental factors also damage these neurons. A striking example of this is MPP+, a well-established neurotoxin that specifically attacks the SNc dopaminergic neurons. For a long time, scientists have focused on paraquat, a neurotoxic pesticide subject to restricted use. Paraquat was originally restricted because it can cause lung damage when workers are exposed to high levels of it in the air, but scientists studying it also noted that it has a strong structural resemblance to MPP+. And sure enough, under some conditions it can cause a Parkinson's-like syndrome in laboratory animals, and a strong and consistent relationship has been found between on-farm exposure to paraquat in farm workers and risk of PD.

Yet, puzzlingly, paraquat doesn't seem to be particularly toxic to dopaminergic neurons when tested directly; much of the rodent data that seems to show such an effect is ambiguous or unlikely to reflect paraquat exposures actually present in the brain. So what might be going on? As it turned out, the scientists were looking in the wrong place. Paraquat, it turns out, doesn't directly kill dopaminergic neurons. Instead, it acts by deranging the cells that are supposed to support and nourish them. Meanwhile, the same thing goes wrong in the aging brain, culminating in Parkinson's and other degenerative syndromes. The lesson here isn't just "avoid exposure to dangerous pesticides." The same study that revealed this surprising indirect mechanism of paraquat's neurotoxicity also showed how much of the harm can be blocked, and in doing so revealed a new tool in our toolbox for taking the "normal" Parkinson's disease of aging out of our futures forever.

Astrocytes are a kind of support cell for the neurons in the brain. They provide a source of nutrients, maintain the equilibrium in the fluids that surround the neurons, participate in neural repair, and take up and release brain messenger-molecules. Scientists discovered several years ago, however, that rising numbers of astrocytes in the aging brain become senescent. Senescent cells lose their normal function in the tissue, cease dividing, and begin secreting a deadly mix of inflammatory and tissue-degrading factors collectively known as the senescence-associated secretory phenotype (SASP) that damages and deranges local tissues.

It was no surprise, then, when scientists found that the burden of astrocytes with tell-tale signs of senescence rises with age in the brain and even faster in those with Alzheimer's disease. Could it also be part of the explanation for the effect of paraquat? And what are the therapeutic implications of such findings in aging people not exposed to this neurotoxin? When the researchers examined the brains of PD patients, they found more cells exhibiting signs of senescence than in people without the disease - and especially astrocytes.

How might one prove that the newly-discovered induction of senescence in astrocytes was responsible for the damage, and not some other direct or indirect effect? The "damage-repair" heuristic of SENS suggested eliminating the senescent cells themselves, and seeing if that was enough to block the downstream mayhem. Research have in fact found that eliminating senescent astrocytes confers benefits to mice with a model of PD that mimics the fundamental processes that drive Parkinson's in aging people. In recent years, researchers have developed so-called "senolytic" drugs that wipe out senescent cells in aging mice and mouse models of age-related disease, exploiting the high dependence of these cells on specific biochemical survival pathways. The benefits of senescent cell clearance to the health and longevity of aging mice have turned out to be more dramatic and sweeping than anyone ever expected.

Link: http://www.sens.org/research/research-blog/save-your-brain-slay-zombie-senescent-cells

Comments

"...all cultural"?! I've noticed that editor is slowly swallowing the red pill that big pharma is not a friend to the SENS community. The want to sell expensive treatments, not find cures or permanent solutions. OK: 10% cultural, but 90% financial.

Posted by: Tom Schaefer at April 12th, 2018 7:16 AM

Well this is great news for mice...

Posted by: Nathan at April 12th, 2018 11:22 AM

@Tom Schaefer senolytics will need re applying periodacly as will other SENS interventions. if its all money BP wants then they will still get it

Posted by: scott emptage at April 12th, 2018 12:46 PM

@Tom Schaefer: Reason is referring to a stage much much before pharma companies enter the picture, when research is done at universities and foundations.

Posted by: Antonio at April 12th, 2018 2:17 PM

I distinctly recall Gary Hudson of Oisín stating in an interview on this site that Oisín's approach would use a drug, specifically a small molecule dimerizer, as a trigger for the transient suicide gene therapy. However, Michael Rae's post states the opposite.

It states "And finally, the inherently transient nature of Oisín's constructs also eliminates the need for a "trigger" drug: you administer the construct when it's time for a round of therapy, and it goes to work right away for a defined window of time before being naturally degraded. The lack of a need for such a drug both reduces the "moving parts" in the system and avoids any unintended effects of the drug itself."

So based off this, I assume Oisín is changing their approach somewhat? Or am I misunderstanding something?

Posted by: Empirical at April 12th, 2018 7:38 PM

@Empirical, and all: no, you're not misunderstanding something and Oisín is not changing anything: you're demonstrating alertness and submitting Michael Rae to some uncomfortable but needed fact-checking. I humbly thank you for catching me in an error, which I will correct forthwith.

Posted by: Michael at April 12th, 2018 9:18 PM

@Empirical @ Michael

Actually you are both correct. In the lab (both in vitro and in vivo) we have used a dimerizer, but we have also tested versions without dimerizer. Both function well. There are applications where one or the other version is preferred, but we're not ready to disclose those.

Posted by: Gary at April 12th, 2018 9:31 PM

1. this is in mice.
other approaches already have a more impressive and consistent result. also are trialed in other mammals or humans.
2. where is the study published? Oisin web or sens web, none of them point at an accepted and peer reviewed published study. looking forward to see the published study.

Posted by: xyz at April 15th, 2018 1:58 PM

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