Tagged: Aging

Are Anti-aging Drugs the Key to Cancer Prevention?

In his recent paper, Dr. Mikhail Blagosklonny explains his perspective on the current landscape of anti-aging drug studies, a key differentiation between healthspan and lifespan variables, and the next steps for human use of anti-aging drugs—beyond clinical trials.

Aging in humans seems as natural as aging in leaves—but is it necessary?
Aging in humans seems as natural as aging in leaves—but is it necessary?
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The process of human aging is a fascinating mystery. Despite all that we do not know, a handful of researchers have dedicated recent decades to the exciting beginnings of solving this biological riddle. One such researcher is Dr. Mikhail Blagosklonny. As a professor of oncology at the Roswell Park Cancer Institute in Buffalo, New York, and Editor-in-Chief at the AgingandOncotarget journals, Dr. Blagosklonny’s mission is to prevent cancer (and other age-related diseases) by inhibiting the aging process—preventing cancer by maintaining youth.

The cover paper chosen for Oncotarget’s Volume 12, Issue #3, is titled, “The goal of geroscience is life extension;” a research perspective written by Dr. Blagosklonny. In this compelling paper, he reflects on the history of anti-aging studies, the differences between drugs that enhance healthspan versus lifespan, and next steps in the human application of anti-aging drugs. 

Hyperfunction Theory of Aging

“According to the geroscience hypothesis, aging is a risk factor for diseases [127]. According to hyperfunction theory, in contrast, aging is a sum of all age-related diseases, not their risk factors.”

Dr. Blagosklonny defines aging as a continuation of human development, driven partially by growth-promoting pathways which drive age-related diseases—he has coined this as the hyperfunction theory.

“Hyperfunction (inappropriate activation) of these signaling pathways directly drive all age-related diseases, which are manifestations of aging. We just need clinically available inhibitors (drugs) of these signaling pathways to extend both healthspan and lifespan, by slowing aging.”

Increasing Lifespan via Increasing Healthspan

Before beginning his interpretation of data from previous anti-aging research studies, Dr. Blagosklonny emphasises the importance of correctly measuring healthspan and lifespan. As indicated in his paper title, the goal of geroscience is to extend lifespan by way of extending overall healthspan.

“Healthspan is a period of life without age-related diseases [27]. It is disease-free survival.”

Healthspan can be difficult to measure due to the nature and hidden course of many diseases. If one particular disease is subdued by treatment in a study and healthspan appears to be increased (through one marker of health or another), this does not guarantee that other age-related diseases have been nullified by this treatment. Dr. Blagosklonny explains that accurate measurements of healthspan are important because, based on the hyperfunction theory, aging is the sum of all age-related diseases.

“After all, aging is an exponential increase of death with age and should be measured by deadly diseases.”

Another point he makes is that many anti-aging drug trials have presented results finding increased healthspan in mice without demonstrating an increase in lifespan. Given that increased healthspan should always lead to increased lifespan, it is not sufficient to only measure healthspan without measuring lifespan in animal studies of anti-aging drugs. If lifespan is not increased, the drug does not demonstrate longevity or anti-aging properties.

“So how is it possible that some senolytics, NAD boosters and resveratrol, increase healthspan without lifespan? The simplest explanation is that they do not increase healthspan at all, because such studies use irrelevant or ambiguous markers of health.”

Over the years, numerous initially promising anti-aging drugs have been tested and debunked by researchers. No compound has continued to withstand the many tests, or has delivered consistent results, quite like the unique bacterium, rapamycin.

Anti-aging Properties in Rapamycin

Rapamycin was discovered in 1964 in a test tube sample of dirt taken from Easter Island—a highly remote volcanic island in the Pacific ocean, west of Chile. Initially looking for antibiotics (often uncovered in the dirt) researchers found the rapamycin bacteria unexpectedly. To their surprise, this new bacteria created a defensive chemical with the ability to affect the activity of a protein and homeostatic ATP sensor called the mammalian target of rapamycin, or mTOR. mTOR is now known to function in regulatory pathways that are responsible for governing cell growth. 

“It was predicted that rapamycin must extend lifespan before it was shown in any animal [105].”

In 1999, rapamycin was FDA approved to regulate hyperimmunity in transplant patients to help enable their immune system to accept a new organ. Since then, rapamycin’s ability to slow cell growth and proliferation has been widely accepted as an anticancer agent and the focus of anti-aging studies in a number of mouse-modeled trials.

“Since 2009, dozens of studies have shown that rapamycin extends medium and maximum lifespan in both males and females in all strains of normal mice tested, as well as in some cancer-prone and short-lived mice [364070].

Other Drugs With and Without Anti-aging Potential

In this paper, Dr. Blagosklonny categorizes a list of seemingly debunked anti-aging drugs with little or no results, including antioxidants, resveratrol, curcumin, quercetin (used alone), and spermidine. He explains that some of these drugs may have potential when used in combination with other drugs in future studies.

He acknowledges potential in berberine (one study found promising initial results), fisetin (clinically available and safe for human use), 17-alpha-estradiol (only results in male mice thus far), acarbose (blocks digestion of complex carbs), enalapril (decreases oxidative damage), losartan (angiotensin receptor blocker), quercetin with dasatinib (clinically available and safe for human use), and metformin. 

“Some life-extending drugs are already approved for human use: supplements (fisetin, vitamin B3 and its analogs), over-the-counter medicine (aspirin) and prescription drugs (rapamycin, metformin, dasatinib, enilopril).”

Dr. Blagosklonny recalls a famous study of metformin where, at a low doses, it increased lifespan in male mice and, at high doses, it ironically decreased lifespan. Metformin was also tested with rapamycin in this study and demonstrated improved results in extending lifespan.

“Yet, a combination of metformin and rapamycin should be re-tested to include a rapamycin-alone group.”

Conclusion

“I expect that a combination of low doses of pan-mTOR and MEK inhibitors with high doses of rapamycin would extend life further compared with rapamycin alone. That could be the next important advance in the anti-aging field since the discovery of anti-aging properties of rapamycin.”

Dr. Blagosklonny believes that researchers should not wait for the lifespan results of clinical trials in humans to begin widespread application of these drugs, since studies already safely display increased lifespan and longevity in mouse models. He is so convinced by rapamycin that Dr. Blagosklonny is currently taking 10 milligrams of rapamycin per week along with his personalized treatment plan, a ketogenic diet, and exercise to jumpstart the next phase of human anti-aging trials within our lifetime. He notes that medical doctors interested in this topic may email Blagosklonny@rapalogs.com or follow him on Twitter @Blagosklonny.

“This article does not represent medical advice or recommendations to patients. The media should exercise caution and seek expert medical advice for interpretation when referring to this article.” 

Click here to read the full research perspective on Oncotarget.com.

Oncotargetis a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues, and other researchers, far and wide.

For media inquiries, please contact media@impactjournals.com.

Trending with Impact: New Plant Extracts Reveal Anti-aging Properties

In search of natural compounds with previously unknown geroprotective properties, researchers used a strain of budding yeast to test 53 plant extracts for their ability to impact the biology of aging and age-related diseases.

Scientist is sampling a chemical extract from organic natural, research and develop background. Scientific concept is sample project about herbal medicine.

The Trending with Impact series highlights Oncotarget 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 and articles about the latest trending publications here, and at Oncotarget.com.

As we age, humans are subjected to a wide variety of age-related diseases, such as arthritis, diabetes, heart disease, kidney disease, liver dysfunction, sarcopenia, stroke, neurodegenerative diseases, and many forms of cancer.

Plant extracts have been consumed for hundreds of years in dietary customs and used as traditional herbal medicines in China and in the Mediterranean. Some of these plant extracts are classified by government health agencies, such as Health Canada, as not only safe for human consumption but also as health-improving supplements with clinically proven benefits to human health. Researchers hypothesized that some of these plant extracts (PEs) may have geroprotective properties. A geroprotector is any compound capable of modulating the root cause of aging and age-related diseases to prolong lifespan in modeled organisms and animals. A couple of well-known potential geroprotectors include melatonin and metformin.

In their previous 2016 study, researchers from Concordia University and Idunn Technologies—both located in Quebec, Canada—screened thirty-five plant extracts and identified 6 as capable of prolonging the length of time a cell can survive, or its chronological lifespan (CLS), and delaying chronological aging in the wild type strain of Saccharomyces cerevisiae budding yeast. On a mission to uncover a new set of plant extracts with geroprotectivity, these same researchers conducted a larger screening of plant extracts in a 2020 study. 

“The objective of the present study was to search for previously unknown aging-delaying (geroprotective) PEs. To attain this objective, we conducted a new screen of many extracts from plants used in traditional Chinese and other herbal medicines or the Mediterranean and other diets.”

The Study

In this study, to learn more about new PEs and the mechanisms of aging and longevity, the researchers continued using the wild type strain of Saccharomyces cerevisiae budding yeast. They explained that S. cerevisiae has short and easily measurable replicative (number of times a cell can divide prior to senescence) and chronological lifespans, is completely sequenced, commercially available, and conducive to comprehensive molecular analyses.

Researchers tested 53 new plant extracts on chronologically aging S. cerevisiae budding yeast. The plant extracts were derived from fruits, berries, beans, herbs, flowers, roots, seeds, leaves, stems, whole plants, bulbs, buds, bark, skins, resin, aerial parts, mushroom bodies, and fermented rice.

“In a quest for previously unknown geroprotective natural chemicals, we used a robust cell viability assay to search for commercially available plant extracts that can substantially prolong the chronological lifespan of budding yeast.”

To determine geroprotectivity from these plant extracts, the researchers cultured, diluted, and fed the budding yeast with glucose. Then, after adding the new PEs, they performed a variety of tests and calculated measurements, including: chronological lifespan assay; oxygen consumption assay; plating assay; quantitative assay; fluorescence microscopy; measurements of the frequencies of spontaneous mutations; glucose concentration measurement assay; age-specific mortality rates; the Gompertz slope; the mortality rate coefficient; and mortality rate doubling time.

Results

“We discovered fifteen PEs that extend the longevity of chronologically aging budding yeast.”

The team was able to identify 15 new geroprotective PEs that have not previously been known for their ability to prolong the lifespan of yeast or other organisms. Based on the results of their measurements and assays, the researchers also identified the cellular processes that these PEs engaged in to prolong the yeast’s chronological lifespan.

“Our study provides evidence that each of the fifteen longevity-extending PEs satisfies all the criteria previously proposed for a CRM.”

CR stands for caloric restriction and CRM stands for caloric restriction mimetics. This means that these new PEs were found capable of mimicking the substantial anti-aging effects that calorie restriction has on organisms and animals, without a reduction in calorie intake.

“Each of the fifteen PEs extends the longevity of chronologically aging yeast under non-CR conditions on 2% (w/v) glucose significantly more efficiently than it does under CR conditions on 0.5% (w/v) glucose.”

They found that the PEs extended the longevity of chronologically aging yeast by decreasing the rate of aging, stimulating a hormetic stress response, intensifying mitochondrial respiration, altering the pattern of age-related changes in intracellular reactive oxygen species, and increasing cell resistance to long-term oxidative and thermal stresses.

“Each of the fifteen geroprotective PEs decreases the extent of age-related oxidative damage to cellular proteins, and many of them slow the aging-associated buildup of oxidatively impaired membrane lipids as well as mitochondrial and nuclear DNA.”

In addition to many more findings, the effects of 15 PEs were found to decrease the frequency of mitochondrial DNA mutations in rib2 and rib3 proteins under non-calorie restricted conditions in S. cerevisiae.

Conclusion

The 15 plant extracts in this study that were newly discovered as geroprotective are as follows: berry extract from a small palm commonly known as Saw Palmetto, extract of the aerial parts from a flowering plant commonly known as the St. John’s Wort, extract from the leaf of Yerba Mate, whole plant extract of Yerba Mate, extract from the leaf of Holy Basil Tulsi, extract from the herb of the perennial plant Solidago Virgaurea, Orange fruit extract, whole plant extract from the common Hop (used in beer), Grape skin extract, whole plant extract from the Green Chiretta, root extract from the perennial Goldenseal herb, Fenugreek seed extract, Barberry root bark extract, extract from the leaf, flower, and stem of the common Hawthorn, and leaf extract from the Red-seeded Dandelion.

“Therefore, we are interested in investigating how different combinations of the fifteen geroprotective PEs described here influence the extent of yeast chronological aging delay. We will be looking for the combinations of geroprotective PEs that exhibit synergistic or additive effects on the extent of yeast chronological aging delay.”

Click here to read the full scientific study, published in Oncotarget.

Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues, and other researchers, far and wide.

For media inquiries, please contact media@impactjournals.com.