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Alzheimer’s Drug Turns Back the Clock in Mitochondria – Article by Steve Hill

Alzheimer’s Drug Turns Back the Clock in Mitochondria – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Mr. Steve Hill discusses an experimental drug, J147, for treating Alzheimer’s disease and also how Alzheimer’s disease is closely linked to aging.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, January 26, 2018

J147 is an experimental drug that has been shown to treat Alzheimer’s disease, and it also appears to reverse some aspects of aging. It is also poised to enter human clinical trials in the near future, although how it works has been somewhat of a puzzle.

A new study  published in the journal Aging Cell has changed all that, and the results are quite intriguing [1]. Researchers at the Salk Institute have solved the mystery of how J147 works and why it makes old flies, mice, and cells more youthful.

Rejuvenating mitochondria

The drug apparently works because it binds to a protein found in mitochondria, the powerhouses of cells; this, in turn, causes cells to function in a more youthful manner. Mitochondrial dysfunction is one of the hallmarks of aging and is thought to be a key reason why we age and develop age-related diseases [2]. This drug appears, at least partially, to address some of that dysfunction.

Finding the target of J147 was the key to revealing the link between Alzheimer’s disease and the aging process. It was the critical information the researchers needed and was holding the drug back from clinical trials.

Dave Schubert, head of Salk’s Cellular Neurobiology Laboratory, and his team originally developed the J147 drug in 2011. The team screened numerous plant-sourced compounds with the potential to reverse the cellular and molecular signs of aging in the brain. The drug was developed as a modified version of a molecule found in the spice curcumin, a common ingredient in Asian foods such as curry.

Since then, the researchers have shown that J147 can reverse memory deficits, increases the production of brain cells, and slows the progression of Alzheimer’s in mice [3]. However, at that point, they did not understand how J147 worked.

Finding the target

During the new study lead by Dave Schubert and Salk Research Associate Josh Goldberg, the researchers used a number of approaches to find out how J147 worked. They eventually identified that the target of J147 was the mitochondrial protein known as ATP synthase, specifically ATP5A, a subunit of that protein. ATP synthase is involved in the mitochondrial generation of ATP, which cells use for energy.

The researchers demonstrated that by reducing the activity of ATP synthase, they were able to protect neuronal cells from a number of toxicities associated with the aging of the brain. One reason for this neuroprotective effect is thought to be the role of excitotoxicity in neuronal cell damage.

Excitotoxicity is the pathological process by which neurons are damaged and killed by the overactivation of receptors for the excitatory neurotransmitter glutamate. Think of it being a bit like a light switch being turned on and off so rapidly that it ends up causing the light bulb to blow.

Recently, the role of ATP synthase inhibition for neuroprotection against excitotoxic damage was demonstrated in a mouse study [4]. The second study showed that mouse models expressing the human form of mutant ATPase inhibitory factor 1 (hIF1), which causes a sustained inhibition of ATP synthase, were more resilient to neuronal death after excitotoxic damage. This data is consistent with this new J147 study, in which an increase in IF1 in the mice reduced the activity of ATP synthase (specifically ATP5A) and was neuroprotective.

ATP synthase is implicated in aging

ATP synthase has previously been shown to influence aging in C. elegans worms and flies. Given that aging is the greatest risk factor for developing Alzheimer’s disease, it is no surprise that the target of the drug is also involved in the aging process.

The team also revealed that by modulating the activity of ATP synthase, they could influence the levels of ATP and other molecules and were able to encourage healthier, more stable mitochondria during aging. Mice given the compound showed profound changes, appearing to look younger at a cellular and molecular level.

The researchers believe that these results are not only encouraging for the treatment of Alzheimer’s, they suggest that J147 may also be useful in treating other age-related diseases.

“People have always thought that you need separate drugs for Alzheimer’s, Parkinson’s and stroke,” said Dave Schubert. “But it may be that by targeting aging we can treat or slow down many pathological conditions that are old-age-associated.”

With J147 having just completed the FDA required toxicology testing in animals, the next step is phase 1 human clinical trials, and the road to approval begins.

Conclusion

It is very heartening to hear important researchers suggesting that in order to treat age-related diseases, one needs to treat the aging processes themselves. This is the exactly what Dr. Aubrey de Grey and others have been saying for many years. It is good to hear more voices joining the call to tackle age-related diseases at their root: the hallmarks and damages where they all begin.

The process of age-related disease begins long before the familiar signs and diagnoses are made; by targeting the early processes that are not given specific disease names, we might yet defeat horrific diseases, such as Alzheimer’s, which rob us of who we are.

Literature

[1] Joshua Goldberg et al. The mitochondrial ATP synthase is a shared drug target for aging and dementia. Aging Cell, 2018 DOI: 10.1111/acel.12715
[2] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
[3] Prior, M., Dargusch, R., Ehren, J. L., Chiruta, C., & Schubert, D. (2013). The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer’s disease mice. Alzheimer’s research & therapy, 5(3), 25.
[4] Formentini, L., Pereira, M. P., Sánchez‐Cenizo, L., Santacatterina, F., Lucas, J. J., Navarro, C., … & Cuezva, J. M. (2014). In vivo inhibition of the mitochondrial H+‐ATP synthase in neurons promotes metabolic preconditioning. The EMBO journal, 33(7), 762-778.

About Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies Steve has provided the community with multiple educational articles, interviews and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity reporter, Psychology Today and Singularity Weblog. He is a co-author of the book “Aging Prevention for All” – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

Stem-Cell Clinical Trials Show Remarkable Results Against Age-Related Frailty – Article by Steve Hill

Stem-Cell Clinical Trials Show Remarkable Results Against Age-Related Frailty – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Mr. Steve Hill discusses two very promising human clinical trials using stem cell therapy for age-related frailty. This article was originally published by the Life Extension Advocacy Foundation (LEAF) .

~ Kenneth Alum, Director of Publication, U.S. Transhumanist Party, October 29, 2017

The first results of two human clinical trials using stem cell therapy for age-related frailty have been published, and the results are very impressive indeed. The studies show that the approach used is effective in tackling multiple key age-related factors.

Aging research has made significant progress in the last few years, with senescent-cell-clearing therapies entering human trials this year, DNA repair in human trials, and a number of other exciting therapies nearing human testing. We are reaching the point where therapies that target aging processes are no longer a matter of speculation; they are now an undeniable matter of fact.

What are mesenchymal stem cells?

Mesenchymal stem cells (MSCs) are one of the most commonly used types of stem cells in therapy. MSCs are adult stem cells that can become other types of cells, depending on stimulus; this ability to become a variety of other cell types is known as multipotency. [1]

The cells into which MSCs can transform (differentiate) include osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells), and adipocytes (fat cells). MSCs are of great interest to aging researchers and are arguably one of the most well studied and understood types of stem cells. [2]

MSCs are currently in various trials to treat conditions such as cancer, heart disease, and arthritis. [3] The potential of MSCs for treating neurodegenerative diseases, such as Alzheimer’s, are also being explored in preclinical testing. [4-5]

A therapy for age-related frailty

The focus of the MSC therapy in the case of these two clinical trials is to reduce the effects of age-related frailty on senior citizens. This also marks an important step for rejuvenation biotechnology, as this is the first stem-cell treatment that is close to final FDA approval for specifically targeting age-related frailty. Should this be approved, then it opens the door for other similar approaches and the potential treatment of many age-related diseases.

The therapy itself uses MSCs taken from adult donor bone marrow and is infused into patients with an average age of 76 years old. The good news is that patients in both the phase 1 and phase 2 clinical trials have shown no adverse effects to treatment.

This is excellent news and now paves the way to move to phase 3 clinical trials, which are larger-scale tests to further determine the efficacy and compare it to the best currently available treatments, for which there are basically none beyond simple coping approaches, such as walking sticks and frames to compensate for frailty.

It is also important to note that at this at this point, the drug or therapy is accepted as having some effect. You can read more about the clinical trial process and what each phase means here.

In the first trial, 15 patients with age-related frailty were given a single transplant of MSCs from donors aged between 20 and 45. [6] Six months later, all patients in the trial showed an improved level of fitness, lower levels of inflammatory tumor necrosis factor (TNF), and improved quality of life in general. TNF is one of the regulators of inflammation and contributes to the chronic age-related inflammation known as “inflammaging”, which drives a number of age-related diseases. [7]

The second trial was a randomized, double-blind study including a placebo group. An improved physical performance level was observed in patients, and, again, the level of systemic TNF, and thus inflammation, was reduced. [8] Once again, there were no adverse effects observed in the patients, and the researchers wrote:

Treated groups had remarkable improvements in physical performance measures and inflammatory biomarkers, both of which characterize the frailty syndrome.

David G. Le Couter and colleagues have written about the clinical trials in a guest editorial in The Journals of Gerontology:

There are always caveats associated with interpreting efficacy in small numbers of subjects, yet it is remarkable that a single treatment seems to have generated improvement in key features of frailty that are sustained for many months.

The next step for the researchers here is to begin a phase 2b clinical trial with 120 patients in ten different locations. Following the conclusion of this, a large randomized phase 3 trial will be launched, and this will be the final barrier to public approval for the therapy.

Conclusion

With an ever-increasing number of aged people in our population, stem cells hold great potential for treating a number of age-related diseases and combating the disability and frailty that accompany the aging process. Developing therapies like these could potentially help older people to enjoy an improved level of physical performance and a better quality of life. Being able to remain mobile and independent as we grow older would be of huge benefit to not only the individual but also to families and society as a whole.

There are currently no FDA-approved treatments for age-related frailty, so this represents a huge unmet need that will only worsen with an increasingly aging population if those needs are not met by new medicines.

Seeing such tangible results in humans is a clear indication of the potential of rejuvenation biotechnology, and how we regard and treat aging will be changing in the near future.

Literature

[1] Nardi, N. B., & da Silva Meirelles, L. (2008). Mesenchymal stem cells: isolation, in vitro expansion and characterization. In Stem cells (pp. 249-282). Springer Berlin Heidelberg.

[2] Stolzing, A., Jones, E., McGonagle, D., & Scutt, A. (2008). Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mechanisms of ageing and development, 129(3), 163-173.

[3] Wang, S., Qu, X., & Zhao, R. C. (2012). Clinical applications of mesenchymal stem cells. Journal of hematology & oncology, 5(1), 19.

[4] Danielyan, L., Beer-Hammer, S., Stolzing, A., Schäfer, R., Siegel, G., Fabian, C., … & Novakovic, A. (2014). Intranasal delivery of bone marrow-derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer’s and Parkinson’s disease. Cell transplantation, 23(1), S123-S139.

[5] Naaldijk, Y., Jaeger, C., Fabian, C., Leovsky, C., Blüher, A., Rudolph, L., … & Stolzing, A. (2017). Effect of systemic transplantation of bone marrow‐derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice. Neuropathology and applied neurobiology, 43(4), 299-314.

[6] Golpanian, S., DiFede, D. L., Khan, A., Schulman, I. H., Landin, A. M., Tompkins, B. A., … & Levis-Dusseau, S. (2017). Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, glx056.

[7] Franceschi, C., Garagnani, P., Vitale, G., Capri, M., & Salvioli, S. (2017). Inflammaging and ‘Garb-aging’. Trends in Endocrinology & Metabolism, 28(3), 199-212.

[8] Tompkins, B. A., DiFede, D. L., Khan, A., Landin, A. M., Schulman, I. H., Pujol, M. V., … & Mushtaq, M. (2017). Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 72(11), 1513-1522.

 

About Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies, Steve has provided the community with multiple educational articles, interviews, and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity Reporter, Psychology Today, and Singularity Weblog. He is a co-author of the book Aging Prevention for All – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.