Steve Hill

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Editor’s Note: The U.S. Transhumanist Party features this article by Steve Hill, originally published by our allies at the Life Extension Advocacy Foundation (LEAF) on January 7, 2019. This article presents the results of a human pilot study that involved the consumption of two promising senolytic drugs, dasatinib and quercetin, to target idiopathic pulmonary fibrosis. The results are promising and constitute a great step forward for senolytics being tested in human clinical trials. Another promising approach is the TAME trial, which is a double-blind randomized controlled clinical trial, to test if Metformin can treat various age-related diseases. 

~Bobby Ridge, Assistant Editor, July 4, 2019

The results from a human pilot study that focused on treating idiopathic pulmonary fibrosis with senescent cell-clearing drugs has been published. The drugs target aged and damaged cells, which are thought to be a reason we age and get sick, and remove them from the body.

Senescent cells and aging

As we age, increasing numbers of our cells become dysfunctional, entering into a state known as senescence. Senescent cells no longer divide or support the tissues and organs of which they are part; instead, they secrete a range of harmful inflammatory chemical signals, which are collectively known as the senescence-associated secretory phenotype (SASP).

Normally, senescent cells destroy themselves by a self-destruct process known as apoptosis before being cleared away by the immune system. Unfortunately, as we age, the immune system becomes weaker, and senescent cells start to build up in the body. The accumulation of senescent cells is considered to be one of the reasons why we age and develop age-related diseases.

It has been suggested that the clearance of senescent cells might help address a number of age-related diseases at once, as senescent cells are thought to be one of the fundamental reasons that we age. Drugs that can remove these unwanted, damaged cells are known as senolytics.

Human trial results for senolytics

This new publication by researchers at the Mayo Clinic, including James Kirkland, one of the pioneers of senolytic drugs, shows the results of a pilot study that uses dasatinib and quercetin to treat idiopathic pulmonary fibrosis [3].

Pulmonary fibrosis causes scarring of the lung tissue, which leads to the progressive loss of lung function over time. When the disease’s origin is unknown, it is called idiopathic pulmonary fibrosis, or IPF. The treatment options for this disease are extremely limited with no currently known cure.

The researchers in this new study tested a combination of dasatinib and quercetin, one of the earliest senolytic drug combinations that was tested in mice and shown to have beneficial results, particularly for the cardiovascular system [4-5]. It was also shown in a previous study that clearing senescent cells using dasatinib plus quercetin was able to alleviate idiopathic pulmonary fibrosis (IPF)-related dysfunction in a mouse model of the disease.

Fourteen patients with IPF were recruited for this pilot study, and the initial results, while leaving room for improvement, are promising.

Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulating SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50).

It should be noted that this was only a small pilot study and that the optimal human dosage and frequency is yet to be established. Typically, the next step is to launch a larger-scale study to establish this dosage.

The researchers also note that these results warrant evaluation of dasatinib plus quercetin in larger, randomized, and controlled trials for senescence-related diseases. In other words, they would like to test senolytics in larger studies for various age-related diseases, and the results certainly support doing exactly that.

Conclusion

These initial results are positive, despite there being plenty of room for improvement. The combination of these two drugs also appears to favor particular cell and tissue types over others, much like other senolytic drugs, which were discovered after dasatinib and quercetin were originally shown to clear senescent cells. It may be that a combination of different senolytics will be needed as a “cocktail” of sorts to fully clear out all the unwanted senescent cells, as different senescent cells appear to use various survival pathways to evade apoptosis, and no single drug can target them all.

We greet these early results positively and look forward to the beginning of larger-scale studies for multiple age-related diseases. Given how senescent cells appear to be implicated in most if not all age-related diseases, there are some exciting possibilities ahead.

Literature

[1] Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., … & Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS biology, 6(12), e301.

[2] Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathological Mechanical Disease, 5, 99-118.

[3] Nambiar, A., Justice, J., Pascual, R., Tchkonia, T., Lebrasseur, N., Kirkland, J., … & Kritchevsky, S. (2018). Targeting pro-inflammatory cells in idiopathic pulmonary fibrosis: an open-label pilot study of dasatinib and quercitin. Chest, 154(4), 395A-396A.

[4] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.

[5] Roos, C. M., Zhang, B., Palmer, A. K., Ogrodnik, M. B., Pirtskhalava, T., Thalji, N. M., … & Zhu, Y. (2016). Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging cell.[/column]

Steve Hill serves on the LEAF Board of Directors and is the Editor-in-Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ Magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Keep Me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.