Tagged: Aging

Oncotarget

Can Mechanisms of Hair Loss Shed Light on Cancer and Aging?

November 29, 2023

In a 2023 study, researchers investigated hair loss and their findings may lead to a better understanding of tissue homeostasis, initiation of cancer and the aging process.

—

Hair follicles are dynamic structures that undergo cyclic phases of growth, regression and quiescence. The growth phase, known as anagen, lasts for several years, followed by a short regression phase called catagen. During catagen, most cells within the follicle undergo programmed cell death, but a small population of stem cells remains viable to replenish the follicle during the subsequent growth phase. Understanding the mechanisms involved in hair follicle regression is not only important for elucidating normal tissue homeostasis but also for studying pathological conditions such as cancer and aging.

In a recent study, researchers Bradley D. Keister, Kailin R. Mesa and Krastan B. Blagoev from the National Science Foundation, The Jane Coffin Childs Memorial Fund for Medical Research, Yale School of Medicine, Johns Hopkins University, Bulgarian Academy of Sciences, and Sorbonne Université shed light on the role of apoptotic cells in hair follicle regression and cell death. Their research paper was published in Oncotarget on October 19, 2023, entitled, “Apoptotic cells may drive cell death in hair follicles during their regression cycle.”

“Here, we use a quantitative analysis of the length of hair follicles during their regression cycle.”

The Role of Apoptotic Cells in Hair Follicle Regression

In this study, researchers suggest that apoptotic cells play a crucial role in driving cell death during hair follicle regression. Intravital microscopy in live mice revealed that the elimination of epithelial cells involves supra-basal cell differentiation and basal cell apoptosis, which are influenced by the synergistic action of TGF-β (transforming growth factor) and mesenchymal-epithelial interactions. The study also demonstrated that the basal epithelial cells are not internally committed to death, and the mesenchymal dermal papilla (DP) is essential in inducing apoptosis.

While the exact mechanism leading to the propagation of apoptosis towards the regenerative stem cell population remains unclear, the researchers proposed a quantitative analysis of the length of hair follicles during their regression cycle. The data obtained from this analysis suggested a propagation mechanism driven by apoptotic cells inducing apoptosis in their neighboring cells. Interestingly, the study found that apoptosis slows down as it approaches the stem cells at the end of the follicle, indicating the presence of a pro-survival signal released by these stem cells.

“In this paper we introduced a mathematical model of the hair follicle regression cycle that postulates that the regression is initiated by the dermal papilla, but that this signal affects only the cells adjacent to it.”

Hair Follicle Regression & Stem Cell Niches

To understand the dynamics of hair follicle regression, it is essential to consider the concept of stem cell niches. Adult stem cells, along with their supporting cells, form these niches, which maintain the functionality of renewable tissues in various organs. Stem cell niches have been identified in organs such as the colon, breast, skin, hair follicles, and bone marrow. Each organ has a distinct stem cell niche architecture, which can influence the rate of aging and susceptibility to cancer.

The study by Keister et al. highlights the importance of stem cell niches in hair follicle regression. The mesenchymal DP cells, located at the bottom of the follicle, were implicated in the initiation of regression through the release of a pro-apoptotic signal, possibly associated with TGF-β. While the DP cells are necessary for the initiation of regression, they are not required for the completion of the regression phase. This suggests that other mechanisms, in addition to the DP signal, contribute to the observed apoptotic propagation.

Quantitative Analysis of Hair Follicle Regression

The team conducted a quantitative analysis of hair follicle length during catagen to gain insights into the dynamics of regression. The study measured the length of hair follicles at two time points separated by 12 hours using intravital microscopy. The data revealed that shorter hair follicles regress at a slower rate compared to longer follicles. This observation suggests that the apoptotic propagation slows down as the dying cells approach the regenerative stem cell pool.

To explain the observed data, the researchers proposed a quantitative model in which apoptotic cells release a local signal that primes neighboring cells for apoptosis. Simultaneously, the stem cells release a pro-survival signal, creating a spatial gradient. This model is consistent with the experimentally measured distribution of follicle lengths and the deceleration of hair follicle regression. The simulations of the model demonstrated that the propagation of apoptosis along the follicle becomes slower and eventually stops when it reaches the stem cells.

The Power Law Distribution of Follicle Lengths

In addition to the quantitative analysis, the researchers investigated the distribution of follicle lengths during catagen. They found that the data obtained from the experiments were consistent with a power law distribution. (Note: The power law refers to the relationship between two quantities, stating that a relative change in one leads to a relative change in the other.) While the power law distribution was observed in the model, it is important to note that the biological lengths of the follicles make it challenging to have high confidence in this distribution. However, the model generated a power law probability distribution function, providing further support for its validity.

Implications & Future Directions

This research paper presents a comprehensive understanding of the role of apoptotic cells in hair follicle regression. The proposed model, which involves the interplay between apoptotic cells and stem cells, provides insights into the dynamics of regression and the maintenance of stem cell niches. Further research is needed to validate the model and explore the potential application to other stem cell niches in different organs.

The findings of this study have implications for the understanding of tissue homeostasis, initiation of cancer and the aging process. By unraveling the mechanisms behind hair follicle regression, researchers can gain valuable insights into the regulation of cell death and renewal in various tissues. This knowledge can potentially lead to advancements in regenerative medicine and the development of targeted therapies for conditions related to abnormal cell death and tissue regeneration.

“In conclusion, hair follicle regression may be governed by cell-cell induced programmed cell death, which slows down as the stem cell compartment is approached and does not affect the stem cell compartment from which the growth phase is initiated. […]. The generalization of the model to different geometries and topologies of different stem cell niches, as well as to the details of their stem cell renewal kinetics can address problems related [to] disease states like cancer and aging.”

Click here to read the full research paper in Oncotarget.

—

Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

Click here to subscribe to Oncotarget publication updates.

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

Mikhail Blagosklonny / Oncotarget

Dr. Mikhail Blagosklonny on Rapamycin Longevity Series

September 7, 2023

Dr. Mikhail Blagosklonny joins “Master One Thing” host Krister Kauppi to discuss the impact of his rapamycin research and hyperfunciton theory of aging.

The world’s leading Rapamycin researcher, Dr. Mikhail Blagosklonny, has a long background in cancer research and one important discovery he made around 2000 was that Rapamycin slowed down senescent cancer cells in different ways. After that step-by-step, his interest in the longevity field increased and he developed the very interesting hyperfunction theory of aging.

He has made a huge contribution in moving the Rapamycin longevity field forward and his research papers have impacted many people. For example, the Rapamycin physician Alan Green who – thanks to these papers – took the decision in 2017 to start prescribing Rapamycin off label. Today, Alan Green has the biggest clinical experience in the area with more than 1,200 patients. A lot of other physicians have after that also taken these steps and one of those, for example, is physician Peter Attia.

Interview Table of Contents:

  • 02:32 Current situation and mission
  • 04:07 Why did Rapamycin not prevent his cancer?
  • 06:33 He develops a new type of cancer treatment
  • 08:32 Hyperfunction theory of age-related diseases
  • 10:38 mTOR drives age-related diseases
  • 13:00 Hyperfunction theory and the car analogy
  • 17:20 Difference between new and old version of hyperfunction theory
  • 19:58 Prediction based on hyperfunction theory
  • 21:38 Rapamycin seems to work at any age
  • 23:55 Rapamycin will not make you immortal
  • 26:21 Rapamycin delays lung cancer in mice
  • 27:44 Hyperfunction theory and hormesis
  • 29:13 Rapamycin combination with fasting or calorie restriction
  • 30:33 Rapamycin combination with Acarbose or low carb diet
  • 31:40 Rapamycin combination with exercise
  • 33:04 Exercise and longevity effect
  • 36:10 mTOR sweet spot
  • 38:44 Why do centenarians live a long life?
  • 40:36 Theory of accumulation of molecular damage
  • 44:04 Hyperfunction theory was initially rejected
  • 47:47 Rapamycin research that is missing
  • 51:44 Rapamycin and bacterial infection
  • 53:30 Rapamycin side effect on longevity dose regime
  • 55:50 Rapamycin and pseudo-diabetes
  • 58:51 Rapamycin combination of Acarbose or low carb diet
  • 1:00:09 Rapamycin and increase in lipids
  • 1:02:19 mTOR, mTORC1 and mTORC2
  • 1:05:22 Mikhail’s self-experimentation with Rapamycin
  • 1:10:41 Rapamycin and traditional medical care
  • 1:11:13 Rapamycin and unacceptable side effects
  • 1:14:26 Rapamycin and combinations to avoid
  • 1:16:55 Rapamycin and high protein intake
  • 1:18:08 Best time to start taking Rapamycin
  • 1:21:00 Does Rapamycin prevent cancer or not?
  • 1:23:52 Autophagy is a double-edged sword
  • 1:26:51 Important insight from his cancer
  • 1:28:38 Rapamycin rebound effect
  • 1:30:24 Difference between theory and practice
  • 1:32:45 Mikhail’s cancer and cancer treatment
  • 1:37:36 Rapamycin and danger

Dr. Blagosklonny’s Links:

Rapamycin resources:

Disclaimer from host Krister Kauppi:

The podcast is for general information and educational purposes only and is not medical advice for you or others. The use of information and materials linked to the podcast is at the users own risk. Always consult your physician with anything you do regarding your health or medical condition.

Mikhail Blagosklonny

Are Anti-aging Drugs the Key to Cancer Prevention?

February 4, 2021

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?
Listen to an audio version of this article

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 [36, 40–70].

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.

Oncotarget

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

January 29, 2021

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.