Revolutionizing Age-Related Disease Management: The Promise of Senolytic CAR T Cells

Revolutionizing Age-Related Disease Management: The Promise of Senolytic CAR T Cells

Recent developments in immunotherapy offer a glimmer of hope in the pursuit of longevity and the alleviation of age-related diseases. Utilizing engineered chimeric antigen receptor T (CAR T) cells, a recent study has shed light on a promising new approach to combating the effects of aging, particularly metabolic dysfunction and decreased physical fitness (Amor C, Fernández-Maestre I, Chowdhury S. et al. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nat Aging. 2024. https://doi.org/10.1038/s43587-023-00560-5).

The Senescence Dilemma and Senolytic Therapies

As organisms age, their bodies accumulate senescent cells—cells that have stopped dividing and that contribute to age-related tissue decline. These cells are not just passive bystanders; they actively secrete inflammatory and debilitating molecules, exacerbating the aging process and contributing to various age-related pathologies. Historically, interventions such as genetic ablation have demonstrated that clearing these cells can improve health outcomes in animal models of aging.

While small-molecule drugs, known as senolytics, have been developed to target and eliminate these senescent cells, their application is hindered by the need for continuous administration. Amor et al. propose a more enduring solution: senolytic CAR T cells.

CAR T cell therapy is an innovative treatment utilizing an individual’s T cells (specialized immune cells) genetically modified in the lab. T cells, extracted from the patient’s blood, are modified with a gene that codes for the CAR component; this modification allows the T cells to recognize a specific marker on the surface of targeted cells. After this genetic alteration, the cells are cultured in the lab to increase their numbers and infused back into the donor. These engineered cells can now efficiently target and destroy cells of interest. This therapy has shown significant success in treating some forms of blood cancer.

uPAR-Targeted CAR T Cells: A Novel Approach to Senolytics

The first step in engineering an efficient CAR T cell therapy is the selection of a target protein. Senescent cells accumulate urokinase plasminogen activator receptor (uPAR) during aging; this study therefore utilized CAR T cells engineered to target cells containing uPAR.

The findings demonstrate that treatment with the anti-uPAR CAR T cells improved exercise capacity in aged mice, as well as ameliorated metabolic dysfunction, such as enhancing glucose tolerance. In addition to aging mice, researchers also looked at this therapy’s effects in the context of a high-fat diet. High-fat diets in mice induce metabolic dysfunction and speed senescent changes. This intervention, when applied to mice on a high-fat diet, showed similar improvements, indicating its broad applicability.

Exploring the Mechanisms

With few exceptions, all cells undergo some form of age-related senescence. The question of which specific uPAR-positive cell populations are responsible for the observed improvements in metabolic function remains unclear. While other studies have linked the elimination of senescent cells in specific tissues, such as pancreatic beta cells or adipose tissue, to improved metabolic outcomes, the current study broadens this understanding to include cells of the immune system.

Interestingly, the study notes that targeting macrophages, the senescent cells of the immune system, might play a significant role in the aging process. The authors believe that the elimination of macrophages contributes positively to the observed health improvements; however, the scope of this study is limited.

Advantageous Therapeutic Application

The unique advantage of senolytic CAR T cells lies in their specific targeting mechanism based on the expression of a particular surface antigen. Beyond this study’s selective targeting of uPAR, the versatility of CAR T allows for the targeting of multiple antigens, potentially providing a means to more specifically target distinct tissue types and cell populations. This feature might allow for a fine-tuning of the specified target, reducing the side effects inherent to traditional pharmacological therapies and improving safety.

The persistence and durability of the effects of uPAR-targeted CAR T cells after a single low-dose treatment underscores the clinical potential of this approach in treating chronic age-related diseases. This innovative therapy could revolutionize the way we approach aging and age-related pathologies, offering hope for more effective, long-lasting treatments. Although promising as a persistent single-dose therapy, the 12-month duration of this experiment limits the ability to interpret both the maximal efficacy of a single treatment and its potential to promote longevity. A more extensive long-term study is required to understand if these acute improvements would translate into lasting health benefits and lifespan modulation.

With an ever-increasing aged population, the need for effective treatments for age-related diseases becomes increasingly critical. The development of senolytic CAR T cells targeting uPAR opens new avenues in the fight against aging and its associated diseases. While further research is needed to fully understand and harness this technology, the prospects are promising, offering a potential paradigm shift in how we address the challenges of aging.

Intermittent Methionine Restriction: A Superior Approach to Bone Health

Intermittent Methionine Restriction: A Superior Approach to Bone Health

An intermittently methionine-restricted diet reduces marrow fat accumulation and preserves more bone mass than continuous methionine restriction, according to a recent study from the Johnson Lab published in Aging Biology.

Methionine restriction (MR) is known to increase the lifespan of multiple species, with an increase of up to 45% observed in rodents. The believed mechanism behind this benefit is the lowering of the hormone IGF-1. In addition to increasing lifespan, MR has also been shown to confer a variety of health benefits. These primarily include protection against metabolic dysregulation, such as obesity, dysglycemia, hyperlipidemia, and hepatosteatosis.

Although the numerous positive benefits of continuous MR outweigh its drawbacks, there are some detrimental effects of this intervention. First, maintaining the exceedingly low levels of dietary methionine required for long-term continuous MR would be challenging, if not impossible, for individuals outside of a controlled laboratory setting. Furthermore, previous studies conducted at OFAS have shown that MR can negatively affect the development of the musculoskeletal system. Specifically, it has been found to impair whole-body growth in mice, leading to reduced maintenance of lean muscle mass and the development of bones that are less dense and more frail.

Research from the Johnson Lab has aimed to address the challenges posed by continuous MR by developing an intermittent methionine restriction (IMR) regimen. Unlike continuous MR, which necessitates a diet continually low in methionine, IMR produces the same benefits but requires only three days of intervention each week (Fig. 1). Designed to make methionine restriction more feasible, the group’s prior studies have shown that IMR provides all of the short-term benefits of continuous MR without compromising lean body mass development. The group’s latest publication investigates whether IMR can also circumvent the adverse effects of continuous MR on bone composition and structural integrity.

Fig. 1: Graphical representation of continuous MR as compared to intermittent MR. Red circles on the calendar indicate days when methionine is restricted.

Intermittent MR Improves Bone Quality

Trabecular bone, also known as spongy bone, features a porous, honeycomb-like structure that provides strength and flexibility. It is primarily located at the ends of long bones and the inner layers of most bones. Cortical bone, or compact bone, on the other hand, is dense and rigid, forming the hard outer layer of bones and providing structural support and protection. In mice, continuous MR is known to impair the formation of both trabecular and cortical bone. In contrast, mice undergoing an IMR regimen do not experience impairment in these types of bone (Fig. 2 and 3).

Fig. 2: Comparison of micro-computerized tomography images of trabeculae from mice treated with continuous MR (MR) and intermittent MR (IMR). Note that MR trabeculae have less bone and greater space in their lattice-like structure. IMR trabeculae have thickness and spacing more similar to that of the control (CF).

Fig. 3: Images depict micro-computerized tomography images of halved femoral head sections. Note that the trabeculae (lattice-like structure comprising the inner region) of continuously methionine-restricted mice (MR) are fewer and more dispersed than that of intermittently methionine-restricted (IMR) counterparts. Also of note, the cortical bone (solid bone around the periphery) of IMR femurs is thicker and more similar to that of the control (CF).

The impairment in the bones of mice under continuous MR is driven by a decrease in bone-producing osteoblasts and an increase in bone-degrading osteoclasts, leading to greater bone resorption and reduced bone formation. In contrast, IMR showed a substantial increase in osteoblasts compared to continuous MR. Despite a similar increase in osteoclasts, the significant rise in osteoblasts with IMR allows for compensatory maintenance of bone formation.

The study also found significant changes in the central cavity of the bone, particularly in marrow fat production through adipogenesis—a process influenced by age, diet, and disease, and linked to bone health and metabolic regulation. IMR significantly reduced marrow fat accumulation compared to continuous MR, suggesting IMR’s potential in preventing the decline in bone health associated with adipogenesis.

Understanding whether these structural changes translated to increased strength was particularly important. Accordingly, direct mechanical strength testing revealed that continuous MR weakened bones, whereas IMR preserved bone strength.

According to the authors, the significance of this study is notable. Contributing author Jason Plummer states, “One focus of our lab’s recent work is to enhance the translation of MR and allow for its benefits to be applied in everyday life. In our previous study, the design of an intermittent methionine-restricted diet achieved a more convenient means of methionine restriction while still sustaining lean body mass. This most recent study demonstrates that intermittent MR also has a similar effect in the preservation of bone structure while maintaining the robust health benefits of continuous MR.” The conservation of these particular physical qualities is especially important in pro-longevity interventions. The author further states, “The loss of lean muscle mass and bone are both well-known and debilitating aspects of aging. Any intervention that promotes longevity but exacerbates those aspects would be highly problematic.”

Canine Companions: Paving the Way for Human Aging Treatments

Canine Companions: Paving the Way for Human Aging Treatments

The FDA has approved a phase I clinical trial to test LOY-003, a novel therapeutic compound to delay aging in dogs. Why is this so important?

FDA Drug Approval and Aging

Some argue that aging is a natural biological process, not a pathological condition; others contend that aging is a disease that warrants medical intervention. Recent years have seen increasing support for the view of aging as a disease or at least as a significant driver of disease. This debate becomes particularly problematic when seeking FDA approval of drugs targeting aging. The FDA’s current regulatory framework is designed to evaluate drugs for the treatment of specific diseases with well-defined endpoints. Besides the contentious status of aging as a disease, the FDA recognizes aging as a complex and multifactorial process. This poses challenges in defining clear endpoints for clinical trials. While there is significant interest in developing drugs that target aging, the regulatory considerations and the complex nature of the aging process present substantial challenges.

To date, most drugs with the potential to delay or improve the aging process have had to find a kind of ‘backdoor’ entry into the FDA approval pipeline. For instance, modified versions of rapamycin—a well-characterized, pro-longevity compound, and part of a class of drugs known as rapalogs—have gained FDA approval for clinical trials by testing their efficacy in preventing viral infections in the elderly, rather than their ability to extend lifespan. The FDA’s approval of a clinical trial aimed at ‘treating’ aging, albeit in dogs, could be a significant step towards paving the way for future human trials.

Exploring the Study’s Foundations and the Importance of Utilizing Dogs

Developed by the veterinary biotech company Loyal, LOY-003, as well as its predecessors LOY-001 and LOY-002, have shown considerable promise in extending the lifespan of large-breed dogs. LOY-003 has received preliminary approval from FDA, based on initial data showing a ‘reasonable expectation of effectiveness.’ It is primarily targeted at dogs aged 7 years and older and weighing at least 40 pounds. It is administered as an injection every three to six months.

The science behind LOY-003 involves the hormone insulin-like growth factor-1 (IGF-1), which contributes to growth but is also linked to aging and longevity. In larger dog breeds, such as Great Danes, IGF-1 levels are significantly higher compared to smaller breeds like Chihuahuas. It is believed that high levels of IGF-1 in adult dogs accelerate their aging process and reduce their healthy lifespan. LOY-003 works by reducing IGF-1 to levels observed in smaller breeds, thereby potentially extending the healthy lifespan of larger dogs. The mechanisms underlying this drug’s actions are particularly interesting, as a large portion, if not the majority, of known interventions capable of extending the lifespan of laboratory animals are thought to work through the IGF-1 pathway. Examples include dietary restriction, metformin, and genetic modifications, as seen in the long-lived Ames dwarf mouse model.

One might ask, “Why dogs?” Dogs offer several advantages as experimental subjects. Like humans, and unlike many standard laboratory animal models, dogs are genetically diverse. This diversity helps to avoid the complication of confounding results due to a narrow genetic background. Additionally, as companion animals, dogs share our environment, thereby accounting for this particular variable as well. Lastly, and specifically in aging studies, dogs have a relatively short lifespan—about 10% of the human lifespan—allowing for a much faster research turnaround.

Although the significance of this trial as an initial step towards further FDA trials focused on aging cannot be overstated, it’s important to remember that the subjects of this study are large dogs with high levels of IGF-1. The benefits of this specific intervention might not be as substantial when applied to humans, given that IGF-1 levels in humans are dynamic over time and may not correlate with those in the study subjects. Considering that humans are already relatively long-lived, it is plausible that they may naturally benefit from lower levels of the hormone targeted by this drug.

The FDA’s approval of the phase I clinical trial for LOY-003, a treatment aimed at delaying aging in dogs, represents a significant milestone in the field of aging research. The outcomes of this trial could pave the way for future human trials, potentially transforming our approach to aging and longevity. This study not only represents an advance in veterinary medicine but also serves as a critical stepping stone in the quest to understand and potentially mitigate the effects of aging in humans.

Unlocking the Secrets of Naked Mole-Rats: Pro-longevity Effects of Hyaluronic Acid

Unlocking the Secrets of Naked Mole-Rats: Pro-longevity Effects of Hyaluronic Acid

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.

Research Position Available

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.

Putting the Brakes on DNA Transcription to Slow the Aging Process

Putting the Brakes on DNA Transcription to Slow the Aging Process

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.