Nov 27, 2023 | Healthspan
Naked mole-rats, those peculiar-looking creatures that live in underground colonies, have fascinated scientists for years. Although appearing perpetually old, these small, wrinkled rodents defy the aging process, living for over 40 years without showing any signs of aging. In contrast, on average a mouse typically enjoys only two years of life. How do naked mole-rats stay youthful and healthy for so long? In this article, we delve into the unique nature of these creatures, exploring the latest research that may unlock the secrets behind their extraordinary longevity and resilience.
One key factor contributing to the naked mole-rat’s remarkable longevity is its ability to repair age-associated damage that accumulates over time. They excel in repairing the damage caused by oxygen free radicals and DNA errors, two major culprits behind aging in most organisms. Even more astonishing is that, despite possessing genes that make them theoretically vulnerable to cancer, naked mole-rats rarely develop this disease. Collaborative research from the University of Rochester, Harvard Medical School, and UCLA is interrogating the role of hyaluronic acid as a molecule responsible for the naked mole-rat’s protracted lifespan and near invulnerability to cancer.
The Hyaluronic Acid Connection
Hyaluronic acid (HA) is a popular ingredient in cosmetics and skincare products due to its exceptional moisturizing properties. A naturally occurring substance in the human body, HA has the ability to hold a significant amount of water, contributing to skin hydration and suppleness. In cosmetics, it is often used in the form of smaller molecules, allowing it to penetrate the skin’s surface and provide deep hydration. While HA applied topically offers noticeable benefits in terms of skin hydration and a more youthful appearance, the recent research on high-molecular-mass hyaluronic acid (HMM-HA) in naked mole-rats hints at the potential for even more profound anti-aging effects when used in this larger molecular form.
While there are several theories about the mechanisms driving naked mole-rat longevity, one theory has gained significant attention recently, thanks to a study published in the journal Nature (Zhang Z, Tian X, Lu JY, et al. Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice. Nature, 2023: 621:196–205 https://doi.org/10.1038/s41586-023-06463-0). This theory revolves around the abundance of HMM-HA in the naked mole-rat’s body. HMM-HA is found in the chemical-rich matrix between cells throughout the naked mole-rat’s body.
Dr. Vera Gorbunova, a professor of biology and oncology at the University of Rochester and a prominent researcher in the longevity field, led a groundbreaking study in which she introduced the naked mole-rat gene responsible for producing HMM-HA into mice. The results were promising.
Benefits of HMM-HA
Introducing the naked mole-rat gene into mice resulted in several remarkable benefits. First and foremost, the altered mice had a significantly lower incidence of cancer compared to the control group. While 70% of the control mice eventually developed cancer, only 57% of the HMM-HA-expressing mice faced this outcome. The most significant improvement was observed in the oldest subset of mice, where the difference was 83% and 47%, respectively.
Moreover, the Has2 mice, as they were called (containing the naked mole-rat gene), experienced a substantial increase in lifespan. Has2 males lived more than 16% longer, females a less robust 9%. The most significant impact was on their healthspan, as they scored better in frailty measurements, mobility, coordination, bone density, and various other indicators of health.
The HMM-HA molecule was found to deliver these benefits by reducing senescence, likely resulting from the observed reduction of inflammation through the modulation of multiple pathways. These changes are thought to improve the quality of immune cells, which act as immunoregulatory agents, fortify defense against oxidative stress, and enhance the integrity of the gut barrier, a tissue normally degraded as part of the aging process.
Apart from changes to genes regulating inflammation and senescence, the forced expression of this molecule also upregulated a variety of genes associated with enhanced longevity, specifically those involved in mitochondrial function.
Future Prospects
This study represents the first instance of a gene transferred from one species to another demonstrably extending lifespan, offering tangible evidence of the remarkable interplay between genetic elements and lifespan regulation.
The introduction of the naked mole-rat gene responsible for HMM-HA into mice resulted in a significant increase in their longevity. This unprecedented achievement not only opens new avenues for understanding the intricate mechanisms of aging but also underscores the potential for cross-species genetic transfers to positively influence lifespan and healthspan in ways previously unexplored.
While these findings are exciting, it is essential to approach the idea of transferring genes from one species to another, especially humans, with caution. Such a process is fraught with inherent risks that necessitate careful consideration and extensive research, the primary concern being the potential for unpredictable and unintended consequences. Genes and their functions are highly complex, and introducing foreign genetic material into a human genome could lead to unexpected mutations, disruptions in essential biological processes, and the development of unforeseen health issues. Furthermore, there is a risk of triggering immune responses or adverse reactions, potentially resulting in allergic reactions or autoimmune disorders. However, the insights gained into the naked mole-rat’s longevity and the role of HMM-HA are valuable.
Understanding the mechanisms through which HMM-HA imparts its benefits could lead to further development of pharmaceuticals that harness the potential of HMM-HA to address aging-related issues in humans. Investigating the secrets of the long-lived naked mole-rat could open doors to other pro-longevity therapies, offering new hope for a healthier and longer life. Although the fountain of youth may still be a myth, the humble naked mole-rat is providing tantalizing clues about the potential for improving our health and lifespan.
Sep 5, 2023 | Healthspan, OFAS News
Dr. Sailendra Nichenametla’s lab at the Orentreich Foundation for the Advancement of Science (Cold Spring-on-Hudson, NY) is hiring a Senior Technician or a Senior Post-doctoral Fellow. Dr. Nichenametla investigates how Sulfur Amino Acid Restriction (SAAR, previously called Methionine Restriction) extends lifespan and confers metabolic benefits. The candidate will work on various SAAR-related projects associated with mechanisms, nutritional aspects, and prevention of diseases, including metabolic diseases, cancers, and proteostatic disorders. Responsibilities include generating data extensively from rodent models and occasionally from in vitro studies and clinical study specimens. Routine daily activities include performing experiments and data analysis, drafting publication-quality manuscripts, assisting in submitting grant proposals, and presenting work at scientific meetings.
Minimum Requirements:
Post-Doctoral Fellow
- A Ph.D. with 2 years of post-doctoral experience.
- Independent thinking (commensurate with career level).
- Demonstrable research experience in biomedical sciences in two or more of the following areas/techniques: nutrition, aging, metabolism (tracer-based metabolic studies), animal colony management, cell culture, and molecular biology.
- At least one paper as first author published during your post-doc position.
- At least 1 year experience working with mice or rats.
- Ability to draft publication-quality manuscripts.
Senior Technician
- Ability to perform various assays related to the research areas mentioned above.
- Ability to quickly learn new assays and develop new methods.
- Excellent attention to detail.
- Independent thinking (commensurate with career level).
- Demonstrable research experience in biomedical sciences in two or more of the following areas/techniques: nutrition, aging, metabolism (tracer-based metabolic studies), animal colony management, cell culture, and molecular biology.
- At least three to four publications demonstrating your contribution to data acquisition.
- At least 1 year experience working with mice or rats.
- Ability to write methods sections of manuscripts, laboratory protocols, etc.
Application Materials:
- Cover letter.
- Full curriculum vitae including education or other academic appointments, complete publication record, and research skills listed in detail.
- PDF files of your previous research representing the qualifications of the position you are applying for.
Email your application materials to ofas@orentreich.org.
Jul 20, 2023 | Healthspan
In the pursuit of unraveling the mysteries of aging, researchers have long been intrigued by the intricate workings of our genetic code. Among the various cellular processes involved, DNA transcription, the conversion of DNA to RNA, has emerged as a focal point of investigation. Recent studies have shed light on the fascinating connection between DNA transcription, aging, and lifespan extension. In a
groundbreaking paper published in
Nature, researchers delve into the molecular mechanisms underlying animal aging and provide insights into potential preventive measures (Debès C, Papadakis A, Grönke S, et al. Ageing-associated changes in transcriptional elongation influence longevity.
Nature, 2023: 616:814–821 https://doi.org/10.1038/s41586-023-05922-y). Their findings reveal a novel aspect of aging, characterized by an age-related escalation in the pace at which DNA is transformed into RNA and its impact on subsequently translated functional proteins.
Unraveling the Transcription Process
To grasp the significance of DNA transcription, it is important to understand its process in simplistic terms. Functionally, DNA serves as a library filled with books containing the instructions for building and maintaining our bodies. DNA transcription can be likened to the process of translating those books into a language that our cells can understand. This process relies on a complex of molecules transcribing the genetic information into RNA molecules. These RNA molecules then serve as blueprints for the translation of proteins that are crucial for various cellular functions.
Histones are a type of protein found in chromosomes. They bind to DNA, help to give chromosomes their shape, and help to control the activity of genes.
The initial stage of transcribing DNA into RNA is more complex than meets the eye, and maintaining its fidelity could be vitally important to aging. To ensure efficient use of space, DNA is tightly packaged around a cluster of proteins known as histones, ultimately forming a structure referred to as the nucleosome. Imagine the nucleosome as a beaded necklace. Each bead on the necklace represents a histone protein, while the string that holds the beads together represents the DNA strand. Beyond the spatial efficiency this design provides, the nucleosome acts as a safeguard, protecting the genetic information from damage and adventitious DNA transcription events. Moreover, as a result of DNA being tightly wrapped around histones, access by transcribing machinery is impaired, and this acts as a meditated regulator of gene expression.
The process of unwinding DNA and priming it for transcription requires a collaborative effort from a multitude of proteins. At the heart of this operation lies RNA polymerase II (Pol II), a molecular complex that traverses along the DNA strand, resulting in an early form of RNA aptly known as pre-RNA.
The research conducted by Debès et al. took a comprehensive approach, examining transcriptional processes across multiple organisms, including nematodes, fruit flies, mice, rats, and humans. Using a technique called RNA sequencing, the team measured the speed of Pol II as it traveled along the DNA in cells of different ages. Their findings revealed a universal trend: Pol II speed increased with age across all species and tissues examined. Regardless of the specific gene or tissue, this acceleration of Pol II emerged as a consistent marker of aging.
The Link Between Transcription Speed and Errors
Along with the increase in Pol II speed came potential errors in the crucial process of splicing, which edits pre-RNAs before they can be translated into functional proteins. Maintaining an optimal speed is crucial for accurate splicing, and any deviation can result in faulty translations of proteins. The authors observed that the risk of bad translations increased with the acceleration of Pol II speed, a phenomenon previously associated with advanced age and shortened lifespan. These findings shed light on the delicate balance required for proper splicing and the potential consequences when that balance is disrupted.
Interventions to Slow Aging
Building upon their discoveries, the researchers devised interventions to counteract the age-related increase in Pol II speed. By comparing human umbilical vein cells and lung cells, they uncovered that as cells age, the nucleosomes responsible for regulating Pol II speed slowly unwind and fall apart. This structural change makes it easier for Pol II to slide along the DNA strand, leading to a boost in transcriptional speed. To test their theory, the team genetically inserted two types of histone proteins into human cells in Petri dishes. This modification created additional “speed bumps” for Pol II, effectively slowing down its pace.
The intervention yielded promising results. Cells with additional histone proteins displayed a decreased likelihood of becoming senescent, a state commonly associated with aging. Furthermore, fruit flies, a widely used model organism for longevity research, showed a notable increase in lifespan when subjected to this genetic modification.
The intricate process of DNA transcription has revealed its profound impact on the aging process and lifespan. The research conducted by Debès et al. provides significant insights into the molecular mechanisms underlying animal aging, highlighting the age-related increase in Pol II speed as a universal marker of aging. Pol II has already been extensively studied in cancer therapy, with several medications tested and approved. These new findings hold significant promise for the development of novel anti-aging drugs and the potential repurposing of existing medications. Leveraging this knowledge, researchers could explore the possibility of repurposing these medications for longevity research, opening up exciting new avenues for anti-aging interventions, and moving one step closer to unlocking the secrets of longevity and promoting healthy aging.
Jun 30, 2023 | Healthspan
Hunger, an innate physiological sensation, has played a crucial role throughout human evolution, ensuring survival by driving individuals to seek food and maintain their energy levels. However, the modern world, with its abundance of food options and easy access to calorically dense meals, presents a stark contrast to the conditions in which we evolved. This juxtaposition has led to a significant challenge: the strong impulse of hunger and its satiation, once vital for survival, has become a detriment to human health. The consequences are evident in the rising global prevalence of obesity, a condition closely associated with various age-related pathologies that can dramatically shorten lifespan. Despite the challenges posed by the modern world’s food abundance and its negative impact on health and lifespan, intriguing research has emerged that harnesses the very sensation of hunger in an attempt to extend both.
Various interventions, such as calorie restriction, intermittent fasting, and amino acid restriction, have demonstrated their potential to extend lifespan, with hunger playing a common but not well-characterized role. In a recent study by researchers from the University of Michigan, the fascinating connection between hunger and lifespan extension was further explored, using fruit flies as a model organism [Weaver KJ, Holt RA, Henry E, et al. Effects of hunger on neuronal histone modifications slow aging in Drosophila. Science, 2023: 380(6645):625-632 https://www.science.org/doi/10.1126/science.ade1662].
Fruit flies, scientifically known as Drosophila melanogaster, have long served as a valuable model organism for studying various biological phenomena. Their short lifespan, genetic tractability, and shared biological mechanisms with humans make them ideal for research purposes. While it’s important to acknowledge the limitations of extrapolating findings from flies to humans, this research nonetheless provides valuable insights that can guide further investigations.
BCAAs are Critical Modulators of Lifespan
The study conducted by Weaver et al. delves into the intriguing relationship between branched-chain amino acid (BCAA) restriction and the lifespan of fruit flies. BCAAs, namely leucine, isoleucine, and valine, are essential amino acids that play crucial roles in protein synthesis and cellular metabolism. These amino acids are vital building blocks for the synthesis of proteins in the body and are involved in numerous physiological processes.
In the context of the study, the researchers focused on exploring how restricting BCAA intake affected the lifespan of fruit flies. By manipulating the availability of BCAAs in the diet of fruit flies, the scientists aimed to elucidate the impact of BCAA restriction on their lifespan and to uncover potential mechanisms involved.
BCAA restriction was found to have a significant impact on fruit fly lifespan. Surprisingly, the results revealed a somewhat paradoxical effect. While calorie restriction is a well-known method to extend lifespan, the fruit flies on a low-BCAA diet exhibited increased appetite and food consumption, a phenomenon known as hyperphagia. Consequently, this increased food intake led to a greater caloric intake compared to flies on a regular diet. Additionally, the low-BCAA diet also resulted in a higher intake of amino acids, making up for the low-BCAA deficit. This would suggest that the activation of hunger and its resultant downstream effects are critical to the enhanced longevity of these animals and might act independently of the nutrients they consume.
Further investigation revealed that isoleucine, one of the BCAAs, acts as a critical signal of food consumption. Depletion of isoleucine triggered an elevation in hunger levels, leading to increased food intake. Remarkably, isoleucine restriction alone induced a state of heightened hunger and extended the lifespan of fruit flies.
Hunger and its Role in Lifespan Extension
To understand the underlying mechanisms of hunger-induced lifespan extension, the researchers delved into the intricate workings of a specific subset of fruit fly neurons known as R50H05 neurons. These neurons are responsible for sensing hunger and transmitting signals related to food-seeking behavior. To investigate the role of these hunger-sensing neurons, the researchers employed the powerful and innovative technique of optogenetics.
Optogenetics involves genetically modifying neurons to express light-sensitive proteins called opsins, which allows precise control over neural activity using light stimulation. Optogenetics provides a unique opportunity to dissect complex neural circuits and unravel the direct effects of specific neurons on various physiological processes.
In the case of this study, the researchers genetically engineered the R50H05 neurons in fruit flies to express opsins that respond to specific wavelengths of light. This genetic modification enabled the scientists to selectively activate the hunger-sensing neurons using light, independently of food availability or dietary manipulations. By using light as a tool to precisely control the activity of the hunger-sensing neurons, the researchers were able to investigate their impact on lifespan extension.
Through optogenetic stimulation of the R50H05 neurons, the researchers observed a remarkable extension of fruit fly lifespan. This finding suggested that the activation of these specific hunger-sensing neurons alone was sufficient to promote longevity, even in the absence of changes in food intake or dietary composition. The use of optogenetics in this study shed light on the critical role played by the R50H05 neurons in regulating lifespan and highlighted the potential for manipulating hunger-related neural circuits as a means of extending lifespan.
The research conducted by Weaver et al. provides intriguing insights into the connection between hunger and lifespan extension. Despite the paradoxical nature of increased food consumption, the restriction of specific BCAAs, particularly isoleucine, appears to be a key driver in triggering hunger-related pathways that promote longevity in fruit flies. By activating neurons associated with hunger sensation, independent of nutritional factors, the researchers demonstrated the ability to extend lifespan. While these findings are preliminary and further studies are warranted, they shed light on the complex interplay between hunger and aging, opening doors for potential therapeutic interventions and strategies for promoting healthy aging.
Jun 12, 2023 | Healthspan
In the realm of scientific understanding, few discoveries have had as profound an impact on our comprehension of life’s sustenance as Antoine-Laurent Lavoisier’s groundbreaking work on oxygen in the late 18th century. Lavoisier, a distinguished French chemist, meticulously explored the properties and behavior of this life-sustaining gas, forever changing our perception of the fundamental element that allows organisms to thrive. With an unwavering commitment to empirical research, Lavoisier revealed that oxygen is an indispensable component of the air we breathe, playing a central role in respiration. Despite the well-established understanding of oxygen’s vital role in sustaining life, recent research has presented intriguing evidence suggesting that limiting this critical element could offer life-extending benefits. While it may seem contradictory to the prevailing knowledge, these new findings have sparked considerable interest and discussion among scientists.
Previous studies have demonstrated that hypoxia delays the senescence of cultured cells and extends the lifespan of simple organisms such as yeast, nematodes, and fruit flies. However, an intriguing study by Harvard University researchers has taken this exploration further by investigating the impact of oxygen restriction on mice [Rogers RS, Wang H, Durham TJ, et al. Hypoxia extends lifespan and neurological function in a mouse model of aging. PLOS Biology, 2023: 21(5):e3002117 https://doi.org/10.1371/journal.pbio.3002117].
Interestingly, the study utilized a fascinating connection between calorie restriction, a known lifespan-extending intervention observed in multiple species, and the activation of hypoxia-induced gene expression and pathways.
Hypoxia and Longevity
Hypoxia-induced pathways are known to offer several benefits in biological processes. These pathways activate in response to low oxygen levels, promoting angiogenesis, enhancing cellular survival, and regulating metabolism. These pathways have also been shown to trigger protective mechanisms in cells, boosting their survival and reducing cell death. Furthermore, numerous animal species utilize these pathways to enter a state of stasis during extended periods of hibernation or shorter periods of torpor.
Apart from laboratory experiments, the natural world has provided compelling examples that suggest hypoxia may confer longevity advantages. Certain animal species that experience hypoxic conditions in their natural habitats have enhanced lifespans. For instance, naked mole rats live in low-oxygen underground environments and exhibit remarkable resistance to age-related diseases. High-altitude birds like bar-headed geese and Andean condors have adapted to thrive in oxygen-deprived areas, displaying extended lifespans compared to their low-altitude counterparts. Diving marine mammals like seals, sea lions, and whales face hypoxia while holding their breath underwater but demonstrate impressive longevity. These examples highlight the connection between hypoxic conditions and enhanced lifespans in various animal species and make hypoxia a good candidate for examination as a lifespan-extending intervention.
Study Details
To explore the effects of hypoxic therapy, a short-lived mutant strain of mouse, Ercc1 Δ/-, was used. Ercc1 Δ/- mice are genetically modified to have a deletion or knockout of the Ercc1 gene. The Ercc1 gene encodes for the protein ERCC1-XPF, which is involved in DNA repair mechanisms. ERCC1-XPF plays a crucial role in the nucleotide excision repair (NER) pathway, one of the cellular mechanisms responsible for repairing DNA damage.
The deletion of the Ercc1 gene in these mice results in reduced or impaired NER capacity. As a consequence, Ercc1 Δ/- mice exhibit accelerated aging and increased susceptibility to various age-related diseases, including neurodegeneration, liver degeneration, and early onset of age-related functional decline. These mice have become an important research model for studying the molecular mechanisms underlying aging and age-related diseases, as well as for exploring potential interventions and therapies.
In this study, mice were housed in specialized environmental chambers where they were exposed to 11% oxygen, representing a significant reduction from the normal atmospheric oxygen level of 21% that mice are typically exposed to. This controlled hypoxic environment led to a robust improvement, of approximately 50%, in the median mortality rate, which refers to the point at which half of the mice in the study population had died. Notably, these results were similar in both male and female mice. Furthermore, the overall survival of these mice was increased by 23%, indicating a substantial enhancement in their longevity compared to mice under normal oxygen conditions.
Aligned with the enhanced lifespan, these mice also exhibited notable improvements in their health. This mutant mouse strain typically experiences an early onset of neurological impairments, resulting in a decline in physical well-being and motor function. However, the hypoxic treatment effectively delayed the onset and progression of these symptoms, preserving their neurological health for an extended period.
Study Limitations
While animal studies often fall short of directly translating to humans, it is especially important to approach with caution the results of using a mutant strain. The model strain used in this study exhibits a compromised ability to efficiently repair DNA damage, leading to an accelerated state of aging. Given this understanding, it is reasonable to speculate that hypoxia treatment might primarily act to support DNA maintenance and repair mechanisms, potentially having a limited impact on the natural aging process itself. Surprisingly, hypoxia treatment did not impact the accumulation of DNA damage compared to the untreated control, nor did it improve senescent cell burden, a key indicator of cellular aging.
While the authors of the study did not identify a direct molecular mechanism explaining the observed improvements in health and lifespan resulting from hypoxia treatment, they acknowledged the need for further investigations. Despite this, the research instills cautious optimism that hypoxic therapy could potentially benefit individuals with neurological pathologies resembling those observed in the mutant mouse strain studied. By delving deeper into the underlying mechanisms, researchers aim to unravel the intricate relationship between oxygen restriction, gene expression, and the extension of lifespan, and through continued exploration, a more comprehensive understanding of the therapeutic potential of hypoxia may be obtained.
Apr 24, 2023 | Healthspan, OFAS News
Senior Scientist Sailendra Nichenametla, Ph.D., has been named as a recipient of the inaugural Hevolution/AFAR New Investigator Awards in Aging Biology and Geroscience Research, presented by the American Federation for Aging Research (AFAR) and Hevolution Foundation. Eighteen three-year awards of US $375,000 each have been granted to support research projects in basic biology of aging or geroscience—a research paradigm based on addressing the biology of aging and age-related disease to promote healthy aging. Dr. Nichenametla will utilize the funds to investigate the role of serinogenesis in regulating lipid metabolism.
The inaugural awards support talented early career investigators at research institutions around the world, including Albert Einstein College of Medicine, Boston University School of Medicine, Mayo Clinic, and the University of Wisconsin-Madison.
“In partnership with AFAR, Hevolution Foundation is excited to strengthen the international pipeline of aging researchers through the New Investigators Awards,” shares Felipe Sierra, PhD, Chief Scientific Officer, Hevolution Foundation. “We want to help fill the void and speed the pace of scientific discovery on the processes of aging by dramatically increasing the research workforce. This initial round of grants is a significant step toward that goal.”
Recipients of the New Investigator Awards were selected through a rigorous, peer-review process. Applications were reviewed by established aging researchers who volunteer their time and expertise to select scientists and research projects that have the greatest likelihood of making significant contributions to help us stay healthier longer as we grow older.
To learn more about Dr. Nichenametla’s research, visit www.orentreich.org/nichenametla-lab. For more information on the Hevolution/AFAR New Investigator Awards in Aging Biology and Geroscience visit www.afar.org/funding-opportunities.
