Trending With Impact: New Drug Combinations Inhibit Stress Proteins

Researchers tested antiviral, anticancer, and immunosuppressive drug combinations that may aid in treating neurodegenerative disorders, including Alzheimer’s disease.

Figure 5. Neratinib and AR12 combine to reduce the expression of HSP90, HSP70, GRP78 and HSP27 via autophagy.
Figure 5. Neratinib and AR12 combine to reduce the expression of HSP90, HSP70, GRP78 and HSP27 via autophagy.

The Trending with Impact series highlights Aging publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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Heat shock proteins (HSPs), also known today as stress proteins, were first observed in fruit flies in the 1960s. After Dr. Ferruccio Ritossa inadvertently subjected a preparation of fruit fly salivary glands to a non-lethal increase in temperature, he discovered a new pattern of chromosomal “puffing.” In 1974, researchers identified the proteins that were encoded by the “puffs” recorded by Dr. Ritossa, and named them heat shock proteins. 

These newfound proteins appeared to only become detectable when the cells were heated. Researchers later learned that HSPs can also be induced by oxidants, toxins, heavy metals, free radicals, viruses, and other stressors. Since its discovery, variations of this genetic system have been found in all bacteria, plants, and animals—including humans. HSPs have been well-studied since this revelation, and researchers now believe these molecular chaperones play important roles in protein refolding, aging-related diseases, and overall longevity. 

“Toxic misfolded proteins are key drivers of AD [Alzheimer’s disease], ALS [Amyotrophic lateral sclerosis], HC [Huntington’s Chorea] and other neurodegenerative diseases.”

Researchers from Virginia Commonwealth UniversityTranslational Genomics Research Institute, and the Banner Alzheimer’s Institute took part in a research study experimenting with combinations of therapeutic agents that may improve neurodegenerative diseases. In 2021, their paper was published in Aging’s Volume 13, Issue 13, and entitled, “Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43.”

“In this paper we examined using isogenic colon cancer cells [with] several existing drugs that function by increasing autophagy and degrading misfolded proteins.”

THE STUDY

“Aberrant expression of chaperone proteins is found in many human pathologies including cancer, in virology and in AD, ALS and HC.”

In this study, researchers tested drugs that have been used preclinically and clinically in several anticancer studies. The drugs used were: AR12, an antiviral chaperone ATPase inhibitor; Neratinib, a tyrosine kinase inhibitor; a combination of AR12 and Neratinib; Fingolimod, an immunosuppressive sphingosine l-phosphate receptor modulator; MMF, monomethyl fumarate; and a combination of Fingolimod and MMF.

The cells they tested these drug combinations on in vitro included Vero cells (African Green Monkey kidney cells), isogenic HCT116 colon cancer cells (genetically manipulated colon cancer cells), and GB6 cells (glioblastoma cancer stem cells). They also used plasmids, antibodies, and siRNAs. Researchers acknowledged that the use of non-neuronal cells may be a limitation of this study.

“Our present studies were performed in non-neuronal cells and as a caveat, it is possible that our data in HCT116 and Vero cells will not be reflective of the same processes in neuronal cells.”

Despite this caveat, results from their research were promising. Some combinations of these drugs were capable of knocking down many disease specific proteins that form toxic aggregates inside cells and in extracellular environments via autophagy. 

CONCLUSION

“As the mechanism of drug-action became clearer it was apparent that these agents should also be tested in neurodegenerative diseases. The entire neurodegenerative field needs rapid translational methods that target the underlying cause of disease, toxic misfolded protein. The findings from this work warrant further testing with a focus on clinical utility.”

Click here to read the full research paper, published by Aging.

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.


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Trending with Impact: Epigenetic Age Decreased in Diet & Lifestyle Study

Researchers conducted an eight-week study on diet and lifestyle among a small cohort of 43 male participants between the ages of 50 and 72.

Happy senior couple buying fresh food at the market

The Trending with Impact series highlights Aging publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

Listen to an audio version of this article

In addition to the well-known personal and social costs of aging, the economic costs of aging are also considerably high. Research finds that investing in delaying aging is much more cost-effective than disease-specific spending. A study found that if Americans as a whole delayed their aging by 2.2 years (while extending healthspan), economic savings over 50 years could amount to a cumulative $7 trillion.

“The growing health-related economic and social challenges of our rapidly aging population are well recognized and affect individuals, their families, health systems and economies.”

Across three countries (the United States, Canada, and Israel), researchers from the Institute for Functional Medicine, American Nutrition Association, National University of Natural Medicine, Ariel University, McGill University, and the University of California, conducted a new pilot study on the effects that diet and lifestyle intervention have on aging among healthy males between the ages of 50 and 72. This research paper was published in Aging’s Volume 13, Issue 7, and entitled, “Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial.”

The Study

The researchers organized a cohort of 43 healthy adult males between the ages of 50 and 72. Half of the participants (n=21) completed an eight-week treatment program, and the other half (control group=22) received no intervention. Interventions within the treatment program included regimented diet, sleep, exercise, relaxation guidance, and supplemental probiotics and phytonutrients. Prior to the treatment program, participants were enrolled in a preliminary education week to become acquainted with the researchers’ prescribed dietary and lifestyle interventions.

“To our knowledge, this is the first randomized controlled study to suggest that specific diet and lifestyle interventions may reverse Horvath DNAmAge (2013) epigenetic aging in healthy adult males.”

Diet Prescription

Researchers prescribed the participants with mostly (not entirely) plant-based diet instructions to consume measured portions of liver, eggs, dark leafy greens, cruciferous vegetables, colorful vegetables (excluding white potatoes and sweetcorn), beets, pumpkin seeds (or pumpkin seed butter), sunflower seeds (or sunflower seed butter), methylation adaptogens, berries, rosemary, turmeric, garlic, green tea, oolong tea, animal protein, and low glycemic fruit. They were prescribed two daily doses of PhytoGanix®, which is a combination of organic vegetables, fruits, seeds, herbs, plant enzymes, prebiotics, and probiotics. A daily two-capsule dose of UltraFlora® Intensive Care, containing Lactobacillus plantarum, was also prescribed.

General guidance included that participants should choose organic food products over conventional, and to consume “healthy” oils and balanced types of fat, including coconut, olive, flaxseed, and pumpkin seed oil. Participants were told to avoid consuming added sugar, candy, dairy, grains, legumes/beans, and to minimize using plastic food containers. In addition, the prescription instructed participants to stay hydrated and not to eat between 7pm and 7am.

Lifestyle Prescription

The participant exercise prescription was a minimum of 30 minutes per day for at least five days per week, at 60-80% intensity. They completed two 20 minute breathing exercises daily, using the Steps to Elicit the Relaxation Response process developed by Herbert Benson, MD. Participants were prescribed to sleep a minimum of seven hours per night.

Measuring Epigenetic Age 

“Currently, the best biochemical markers of an individual’s age are all based on patterns of methylation [5].”

To extract DNA from the participants, researchers collected saliva samples and evaluated their RNA and DNA. They used methylation kits, assays, and the Horvath DNAmAge clock to conduct genome-wide DNA methylation analysis and calculate epigenetic age (DNAmAge) at the beginning of the study, and at the end.

“Horvath’s DNAmAge clock predicts all-cause mortality and multiple morbidities better than chronological age. Methylation clocks (including DNAmAge) are based on systematic methylation changes with age.”

Conclusion

According to the Horvath DNAmAge clock, participants in the treatment group scored an average 3.23 years younger at the end of the eight-week program when compared to participants in the control group. While these findings are meaningful, additional studies with a larger cohort size, longer duration, and other human populations will be needed in order to confirm these results.

“Notably, the shorter timeframe of this study and the scale of potential reduction, while modest in magnitude, may correlate with meaningful socioeconomic benefits, and appears to have the potential to be broadly achievable.”

Click here to read the full study, published on Aging-US.com.

Click the links below for more information on corresponding author, Dr. Kara Fitzgerald:
Biological Aging Summary | Instagram | Facebook | Twitter | General Site | Younger You Program

Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

For media inquiries, please contact [email protected].

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