COVID-19 and Aging

A message from Edward James Olmos

Why is the novel coronavirus so deadly to the elderly?

A pandemic has swept the globe, infecting millions and leaving over five hundred thousand dead. In response, millions wait in lockdown at home, while millions more brave the risk of infection to deliver food, medicine, electricity, clean water, and other essential services. A growing number of health workers, meanwhile, face the disease head-on in our hospitals, fighting to save patients from “drowning on dry land.”

All wait in anticipation for the scientists, who labor at a pace that is both record-breakingly rapid yet frustratingly slow to bring us a way out: a drug, a vaccine — a hope.

Through all the daily updates on the sick and the dead, on testing and hospital capacity and changing public health guidance, there remains one constant: by far the greatest predictor of death from this plague is age. The so-called comorbidities predisposing patients to death from COVID-19 — chronic lung diseases, damaged kidneys and hearts, high blood pressure, diabetes — are themselves aspects of aging, erupting in their distinctive ways in particular tissues. Flattening this “demographic curve” of degenerative aging would reduce COVID-19 to a disease similar in impact to an average recent flu season (and make future flu seasons less deadly), while also putting an end to the staggering toll of age-related death and debility that ticks on in the background even now, day in and day out, pandemic or none.

Ending that toll is our mission. At SENS Research Foundation, we develop rejuvenation biotechnologies: new therapies that will repair the accumulated cellular and molecular damage in our tissues and restore youthful function.

The SARS-CoV-2 pandemic is both an immediate, pressing danger, and a call to action. It demonstrates the critical need for better long-term strategies for addressing threats to human life. As members of the global scientific community, all of us at SRF acknowledge the need to adapt and apply our expertise and experience to the current crisis. (SARS-CoV-2 is the coronavirus that causes the disease called SARS-2 or COVID-19.)

Below, we outline some of the ways in which specific forms of aging damage are relevant to diseases like COVID-19 – and how some of our research programs may help render this and other viruses far less dangerous in the future.

Aging’s effect on COVID-19 mortality rate, and the anticipated effects of future rejuvenation biotechnologies.

Data taken from Lancet Infect Dis 2020 Mar 30. pii: S1473-3099(20)30243-7

Comorbidity by age group.

 Image credit: Lancet 380(9836):37-43.

Ending that toll is our mission. At SENS Research Foundation, we develop rejuvenation biotechnologies: new therapies that will repair the accumulated cellular and molecular damage in our tissues and restore youthful function.

The SARS-CoV-2 pandemic is both an immediate, pressing danger, and a call to action. It demonstrates the critical need for better long-term strategies for addressing threats to human life. As members of the global scientific community, all of us at SRF acknowledge the need to adapt and apply our expertise and experience to the current crisis. (SARS-CoV-2 is the coronavirus that causes the disease called SARS-2 or COVID-19.)

Below, we outline some of the ways in which specific forms of aging damage are relevant to diseases like COVID-19 – and how some of our research programs may help render this and other viruses far less dangerous in the future.

Rejuvenate the Immune System

The most obvious link between aging and COVID-19 is the aging of the immune system, or immunosenescence. Older people mount a much weaker and less complete immune response to both infection and vaccine, even as they suffer increasingly from overactive parts of the immune response, including autoimmunity and chronic inflammation. SENS Research Foundation has sponsored several projects aimed at developing damage-repair technologies to restore immune function, including pilot studies of a T-cell “scrubber” that might clear out a specific class of dysfunctional T-cells and early-stage work toward a tissue-engineered thymus, along with a pilot animal study to simulate the effects of both of these interventions.

In today’s pandemic, COVID-19 patients suffer from an exhaustion of natural killer (NK) and CD8+ (“killer”) T-cells. Whereas T-cells and B-cells are specialists, focused on eliminating specifically-identified threats (such as cells infected with specific viruses), NK cells are sentinels patrolling the perimeter of a military camp, on the lookout for anything that looks like it doesn’t belong. Thus, NK cells attack abnormal cell types such as cancer cells, cells infected by viruses like SARS-CoV-2, and senescent cells — that is, cells that have undergone changes that prevent them from replicating, and that spew out a witches’ brew of inflammatory signaling molecules, growth factors, and enzymes that break down proteins. This brew is called the senescence-associated secretory phenotype, or SASP.

Long before the pandemic hit, we knew that NK cells lose much of their effectiveness with age, meaning that aging people already come into the fight against infections like SARS-CoV-2 with these critical early responders weakened. At our Research Center, Dr. Amit Sharma and Elena Fulton have been developing strategies to rejuvenate and reinforce NK cells in aging people. They recently collected preliminary data showing that the proportion of NK cells exhibiting markers of strong cell-killing ability declines sharply with age. To confirm this preliminary finding, they will look for an age-related reduction in NK cells’ ability to kill senescent cells, using NK cells freshly isolated from young adult, middle-aged, and older people. They will run parallel tests on NK cells from the spleens of young (6 months) and old (24 months) mice. Moving from basic research to anti-aging intervention, the team is developing strategies to enhance senescent-cell-killing ability in old NK cells. They will test rejuvenation strategies including adoptive transfer of young NK cells into aging mice, and agents that sidestep the protective shielding that senescent cells throw up to defend themselves against NK cells. If transferring young NK cells works as a proof of concept, it would support moving forward by adapting immune transfer biotechnologies already in use for cancer therapies to instead selectively target senescent cells.

Purge Senescent Cells

For Younger Lungs...

Some of the rejuvenation strategies being tested by Elena and Dr. Sharma will likely enhance aging NK cells’ ability to eliminate any kind of abnormal cell, including those infected by SARS-CoV-2. But the SENS lab is focused on rejuvenating the capacity of NK cells to eliminate senescent cells because of their broad role in driving aging pathology, and it’s not a coincidence that many of their ill effects directly impact a person’s vulnerability to COVID-19.

First is senescent cells’ role in driving fibrosis in our tissues. Multiple aspects of lung function decline with age, while fibrosis increases. Accordingly, diseases of the lung — including chronic obstructive pulmonary disease, lung cancer, and most especially idiopathic pulmonary fibrosis (IPF) — are profoundly age-related. Preliminary evidence suggests that the lung is one of the tissues most burdened with senescent cells with age in humans — a burden further exacerbated by IPF.

We’ve known for a while that the age-related loss of lung function is a massive driver of risk of death from pneumonia. Aging people not only have fewer functional alveoli available, but progressively lose the ability to inhale and exhale deeply to compensate for alveoli taken offline by the infection. Continuing research suggests that eliminating senescent cells in the lung may preserve and restore youthful lung function, leaving the lungs better prepared to endure the attack of the SARS-CoV-2 virus and other causes of pneumonia.

Senolytic drugs, which selectively kill senescent cells, have been shown to reverse lung fibrosis and other tissue fibrosis in aging mice. Studies in aging mice with inbuilt “suicide genes” demonstrate that ablating senescent cells in aging mice restores youthful lung compliance, suggesting an opportunity to do the same with other senescent-cell elimination strategies, such as restoring the ability of NK cells to eliminate them from tissues. Further supporting this, lung fibrosis is partially reversed by two different senolytic drugs in mouse models of IPF, and a third senolytic partially reversed lung fibrosis in mice whose lungs have suffered radiation damage.

... and a Rejuvenated Signaling Environment

In addition to lung damage, another way that senescent cells may exacerbate COVID-19 involves the SASP cocktail of abnormal secretions. One important component of the SASP is an inflammatory factor called IL-6, which rises with age and predicts the risk of frailty and death even without SARS-CoV-2 infection. Now a new report indicates that a hospitalized COVID-19 patient’s IL-6 level is a strong risk factor for going on to require a ventilator, suggesting that senescent cells make aging people more vulnerable to the disease, and that senescent cell ablation could shore up this vulnerability. These findings are so compelling that some clinical centers treating critically ill COVID-19 patients are making experimental use of monoclonal antibody therapies such as tocilizumab and sarilumab, which block IL-6’s access to its receptors. But if we restore NK cells’ ability to eliminate senescent cells, people infected with SARS-CoV-2 would start off with lower IL-6 levels more characteristic of a young person, and thus better prepared for the fight.

In addition to IL-6, it’s recently been discovered that there is a network of factors emitted in the SASP that trigger the formation of blood clots and impede the countervailing factors that dissolve them. It’s long been known that an imbalance in these factors becomes increasingly common as people age, especially if they have risk factors for cardiovascular disease. The discovery that the SASP could tip the balance toward excessive coagulability, combined with the fact that aging people’s tissues become increasingly riddled with senescent cells over time, suggests that senescent cells and their SASP may be a key driver of this process.

Senescent cells’ possible culpability in the pro-clotting bias in aging people’s blood was already an important avenue for research before the rise of COVID-19, since the excessive tendency to form and maintain clots puts them at greater risk of heart attack, stroke, and venous thromboembolism (VTE) — abnormal clots forming in the veins. But it becomes a matter of acute focus in the face of multiple reports that high levels of markers of excessive clotting are common in COVID-19 patients at hospitalization, and foreshadow admission to the ICU and death from or with COVID-19 (in Holland and in Wuhan). Indeed, despite receiving prophylactic anti-clotting medication, nearly a third of Dutch patients with COVID-19 suffered from dangerous blood clots, including very commonly VTE that work their way up to cut off the lung tissue’s own blood supply, starving the lung itself of oxygen even as it is under attack by the virus and the patient’s own immune system.

Medical researchers have suggested a number of possible causes of excessive clotting specific to COVID-19, but as usual, the role of aging itself has been almost entirely ignored, despite the powerful influence of age in one’s risk of dying of the disease. Older people’s burden of senescent cells, the recent research suggests, may be predisposing them to a clotting crisis if infected by SARS-CoV-2.

Fortunately, the same research that originally identified the pro-clotting cocktail in the SASP also suggests that rejuvenation biotechnology could eliminate the associated risk of dangerous blood clots. Mice, like people, suffer a rise in senescent cell burden when given the chemotherapy drug doxorubicin, which then release SASP factors that favor the formation and stability of blood clots. In response, the mice produce higher levels of clot-initiating platelets, and those platelets are placed on a hair trigger. Activating a senescent-cell-destroying suicide gene prevented all of these things from happening, suggesting that purging aging cells from aging people could also leave them better prepared to survive an infection with SARS-CoV-2.

Work is already underway to translate these exciting results into human rejuvenation therapies. Mayo Clinic researchers last year conducted a very early-stage clinical trial of drugs that trigger self-destruction of senescent cells in human patients with IPF. Although there were few clearly apparent benefits to senolytic therapy in this study, it was too short-term and involved too few patients (just 14) to expect anything obvious: happily, the researchers are working to expand this pilot study into a larger clinical trial, and other such trials are underway in patients with kidney disease and osteoarthritis, diseases also driven by senescent cells. We will soon begin seeing what these therapies can do to maintain our health and resilience against the forces of degenerative aging and COVID-19.

Trigger Self-Destruction of Mutation-Prone Cells

More than half of the human genome is invasive genetic data left behind by viruses, including millions of retrotransposons. Retrotransposons are “dead” DNA, but their long- and short- interspersed virus-like repetitive elements (LINEs and SINEs) encode machinery that —under certain circumstances — allows them to reactivate, replicate, and spread through the genome. These reactivation events can cause mutations in our functional genes and even disrupt the normal expression of non-mutated genes, leading to cancer, cellular self-destruction (apoptosis), and cellular senescence.

To develop a proof of concept for a new class of “retrolytic” drugs that would ablate these cells before they can further damage the body, SENS Research Foundation is sponsoring work by Dr. Andrei Gudkov and his team at the Roswell Park Comprehensive Cancer Center for a suicide-gene system similar to the groundbreaking INK-ATTAC system that paved the way for the senolytic revolution. As a side-benefit, the gene whose expression will activate the retrolytic suicide gene is also activated in cells with active viral infection (such as SARS-CoV-2), which may eliminate such cells before they are hijacked by the virus to replicate itself.

Transplant Mitochondria to Rescue Critical Lung Cells

Recent gene-expression and protein distribution studies demonstrate that the ACE2 receptor — the critical loophole through which the SARS-CoV-2 virus slips into our cells — is more enriched in a type of lung cell known as AT2 cells, and COVID-19 patient autopsy reports indicate that these cells are subject to a terrible assault during the disease. AT2 cells are critical support cells for type I alveoli — the tiny air sacs that expand and contract to effect gas exchange and respiration. AT2 cells produce the pulmonary surfactant that allows type I alveoli to expand again after contraction by reducing alveolar surface tension. This surfactant also facilitates the exchange of gases between the oxygen-poor, CO2-enriched venous blood and the relatively oxygen-rich air in the lungs; we believe the virus’s assault on these cells is a major contributor to respiratory failure.

It’s these same AT2 cells that fail in an animal model of septic pneumonia, and these mice are rescued by transplanting bone marrow stem cells that donate their mitochondria to the failing AT2. Dr. Amutha Boominathan and Nana Anti of our mitochondrial mutation rescue team have been developing our mitochondrial transplantation protocol. Their initial target is different, but we hope it will treat many conditions of acute energy depletion, as is already being done in small open clinical trials for babies with heart damage from ischemia-reperfusion injury.

Conclusion

Like the pandemic, aging touches all of us. It creeps silently through our tissues, progressively crippling our minds and bodies, and eventually killing us if we don’t die first of accident, violence, or other abrupt age-independent causes. In COVID-19, the damage caused by aging is the largest factor in determining who lives and who dies, even if the trigger was pulled by a virus spread by globalization. The need for rejuvenation biotechnologies as part of medicine has never been clearer, and so we strengthen our resolve. Restoring our cells and tissues to youthful vigor will allow us to step out of our ancient lockdown and into a bright future.

Watch the space below for announcements and progress.

Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy.
Onder G, Rezza G, Brusaferro S.
JAMA. 2020 Mar 23. doi: 10.1001/jama.2020.4683. [Epub ahead of print] PubMed PMID: 32203977.

The dramatically higher case-fatality rate for COVID-19 in Italy as compared with anywhere else in the world (including in the epicenter of the pandemic in Wuhan, China) has been the subject of much speculation and concern. These investigators find the phenomenon to be almost entirely explained via the age structures of the populations, with a much larger share of persons aged >65 in Italy. Looking within each age group, the case-fatality rates in Italy and China are highly comparable for all persons >65, but were higher in Italy in persons age >70 and even more so in those >80 years; these numbers are skewed, however, by the particularly low number of people in these age groups in China as a share of persons >65, and especially the lack of any patients aged >90 in the Chinese reports, who were at very greatly increased risk of death in Italy.

Convalescent plasma transfusion for the treatment of COVID-19: Systematic review.
Rajendran K, Narayanasamy K, Rangarajan J, Rathinam J, Natarajan M, Ramachandran A.
J Med Virol. 2020 May 1. doi: 10.1002/jmv.25961. [Epub ahead of print] Review. PubMed PMID: 32356910.

Convalescent plasma is a very old therapy, first used for diphtheria in the late nineteenth century. Doctors often turn to it for new infections in the absence of established medical therapy, and this has been the case in COVID-19. Available studies appear generally favorable, but are all very small and have no control group, and the evidence for convalescent plasma in most diseases is weak; it was used successfully to treat Ebola, but in a randomized trial of 140 children and adults, it was found no more effective against influenza than control plasma from uninfected subjects. Importantly, it did seem to have salutary effects in the original SARS virus, including some controlled trials; however, none of the trials were of high quality. Three randomized controlled trials are underway in the United States to test the intervention: one to protect medical workers who are not yet infected from the disease, and two in hospitalized patients at different stages in the disease progression.

 A key limitation of the therapy is the low ratio of recovered patients compared to those needing therapy; if it works, it could be the basis for a monoclonal antibody therapy, which could be scaled up to treat far more patients and could likely be made more effective. It would also provide some preliminary confidence for the possibility of a vaccine, whose prospects are uncertain at this time. Fortunately there has been no evidence of antibody-dependent enhancement (ADE) in the use of convalescent plasma for either SARS or COVID-19, although ADE was observed in animal models of SARS and in response to an experimental SARS vaccine in nonhuman primates.

Revel Pharmaceuticals Launched

Glucosepane crosslink breaker research graduates from top Yale lab into the biotech world

Kizoo Technology Capital leads seed round financing at Revel Pharmaceuticals

SAN FRANCISCO/NEW HAVEN/BERLIN, Jan. 21, 2020 — For the past 10 years, Yale Professors David Spiegel and Jason Crawford have been working on tools to enable the development of glucosepane-cleaving drugs. Kizoo Technology Capital investors say now is the time to advance this groundbreaking research toward the clinic and are leading funding of a new company, Revel Pharmaceuticals Inc., founded by Drs. David Spiegel, Jason Crawford, and Aaron Cravens.

Kizoo leads the seed financing round at Revel, with Oculus co-founder Michael Antonov participating. SENS Research Foundation provided funding to the YaleGlycoSENS group for several years.

Glucosepane Biology in relation to Aging and Disease

The long-lived collagen proteins that give structure to our arteries, skin, and other tissues are continuously exposed to blood sugar and other highly reactive molecules necessary for life. Occasionally, these sugar molecules will bind to collagen and form toxic crosslinks that alter the physical properties of tissues and cause inflammation. As a result, tissues slowly stiffen with aging, leading to rising systolic blood pressure, skin aging, kidney damage, and increased risk of stroke and other damage to the brain.

Perhaps the most important of these Advanced Glycation End-products (AGE) crosslinks is a molecule called glucosepane. Revel is developing therapeutics that can cleave glucosepane crosslinks thus maintaining and restoring the elasticity of blood vessels, skin, and other tissues, and preventing the terrible effects of their age-related stiffening.

Revel opens a new category in the SENS repair approach to aging

The Yale group’s first major milestone – the first complete synthesis of glucosepane – was highly recognized when published in Science. Since then progress has been rapid, with development of glucosepane binding antibodies and discovery of therapeutic enzyme candidates capable of breaking up glucosepane crosslinks. Revel will build upon this progress by advancing the first GlycoSENS therapeutics into the clinic.

This is truly a first. We are proud to help Revel open an entirely new category in repairing a significant damage of aging – crosslinking of collagen. Glucosepane crosslinks may cause not only wrinkles on your face but also lead to age-related rising blood pressure and possibly stroke.” says Frank Schueler, Managing Director of Kizoo Technology Capital.

David Spiegel, MD, PhD, Professor of Chemistry at Yale University and Revel founder says: “We are delighted to join Kizoo in building a world-class team to advance crosslink-breaking therapeutics into the clinic. These first-in-class agents have enormous potential to help patients suffering from a wide range of diseases.

Collagen is the infrastructure of our bodies – in every tissue, supporting cellular function and health – but with aging, this critical molecular infrastructure accumulates damage. By clearing out this damage, we can restore tissue function and repair the body. Revel is one of only a few companies taking a repair-centric approach to treat diseases of aging and one day our AGE-cleaving therapeutics will undo this damage at the molecular level.” says Aaron Cravens, co-Founder of Revel Pharmaceuticals.

About Revel

Revel Pharmaceuticals is a biotechnology company located in San Francisco, CA. with a technology platform based on the work of Yale Professors David Spiegel and Jason Crawford. We are commercializing therapeutic designer enzymes to degrade molecular damage that accumulates with aging. By addressing one of the hallmarks of aging, Revel is strategically positioned to develop therapeutics for multiple diseases of aging including osteoarthritis, kidney disease, cardiovascular disease, skin aging, and complications of diabetes.

See www.revelpharmaceuticals.com

About Kizoo

Kizoo provides mentoring and seed and early-stage financing with a focus on rejuvenation biotechnology. Having been entrepreneurs, VCs, and mentors in both high-growth tech and biotech companies for many years, with multiple exits and massive value created for the founders, Kizoo now brings this experience to the emerging field of rejuvenation biotech – a young industry that will eventually become much bigger than today’s largest technology markets.

As part of the Forever Healthy Group, Kizoo directly supports the creation of startups turning research on the root causes of aging into therapies and services for human application. Investments include AgeX, FoxBio, Turn.bio, Elevian, Oisin Biotechnologies, Underdog Pharmaceuticals, MAIA Biotechnology, and others.

Forever Healthy’s other initiatives include the evaluation of new rejuvenation therapies, evidence-based curation of the world’s cutting-edge medical knowledge, funding research projects on the root causes of aging, and hosting the annual Undoing Aging Conference.

For more information, please visit kizoo.com and forever-healthy.org

Contact:
Frank Schueler
Managing Director, Kizoo Technology Capital GmbH
Amalienbadstr. 41, 76227 Karlsruhe
[email protected], +49 721 51600

Underdog Pharmaceuticals Launched

Novel therapeutic approach to cardiovascular disease from SENS Research Foundation flagship research program graduates from laboratory to the biotech world

Kizoo Technology Capital leads seed round financing at Underdog Pharmaceuticals

SRF announces leadership appointments

MOUNTAIN VIEW, Calif., Nov. 14, 2019 (GLOBE NEWSWIRE) — Underdog Pharmaceuticals, Inc. (Underdog), and SENS Research Foundation (SRF) today announced the launch of Underdog and the completion of its seed round, providing $3.95 million to promote Underdog’s development of disease-modifying treatments for atherosclerosis and other age-related diseases. SRF also announced two senior appointments.

The Underdog round is led by Michael Greve’s Kizoo Technology Capital, part of the Forever Healthy Group and one of the premier organizations focusing on accelerating rejuvenation biotechnologies. It also includes Oculus co-founder Michael Antonov through Tubus, LLC, and financier Harald McPike through Chambray Worldwide, Ltd.

Underdog was built from an SRF flagship program that has driven two years of applied development designed to explore and repair the underlying causes of cardiovascular disease. Its co-founders are Matthew O’Connor, Ph.D. and Michael Kope, formerly the V.P. of Research and the founding CEO, respectively, of SRF.

“We’ve taken a well-known and extremely safe compound,” said O’Connor, “and have created novel derivatives that can specifically target the toxic biomolecule that drives the development of atherosclerosis, the cause of most heart attacks and strokes.”

Underdog’s research has combined computational and synthetic chemistry programs to create custom-engineered cyclodextrins (polysaccharides with known industrial and pharmaceutical excipient uses) to capture, and remove from cells, oxidized cholesterol derivatives such as 7-ketocholesterol, which are broadly toxic molecules with no known biological function. “Underdog will take a classic pharmaceutical approach and use it to attack the root causes of cardiovascular disease,” said Kope. “If we’re successful, we won’t just be ameliorating the disease, but reversing it.”

Underdog’s advisors include world-renowned cyclodextrin expert Dr. Lajos Szente. “This elegant approach has the potential to be truly revolutionary,” Szente said. “I’m delighted to be working with them on this important advancement in the field.”

“I came to Aubrey de Grey years ago so that we could work together to accelerate the availability of human rejuvenation therapies,” said Greve. “I am proud to help SRF grow a flagship research program into a genuine company and to help unlock the required capital to develop a true rejuvenation therapy. I’m gratified that we’ve done this while continuing to allow for the health and growth of SRF itself, one of our most important engines for the rejuvenation pipeline.”

The agreement between the organizations will provide equity, royalties, and milestones for the future support of SRF programs.

As Underdog spins out, the V.P. of Research position at SRF has been assumed by Prof. Alexandra Stolzing. Stolzing, a long-standing SRF Research Advisory Board member, received her PhD from the Humboldt University in Berlin, was a postdoctoral fellow at Sheffield University, UK, group leader at the Fraunhofer Institute for Cell Therapy and Immunology, Germany, and then Professor for Biogerontological Engineering at Loughborough University, UK. With over 70 peer-reviewed publications, she has participated in several international research consortia in areas including regenerative medicine, cell and gene therapy development, and neurodegenerative diseases. Her industry experience includes startup CSO and VP of Research roles. Said Stolzing, “I’ve always been passionate about translational research in aging, and I’m very excited to join SRF, where I look forward to translating SRF’s basic science projects, initiating new projects, and helping generate the next wave of healthspan spinouts.”

Science and technology investor and longtime SRF board member Jim O’Neill has stepped in to lead the SENS Research Foundation as interim CEO. He will also spearhead the search for the incoming permanent CEO. O’Neill has advised, invested in, and nurtured more than sixty science and technology companies. While running the Thiel Foundation, he co-founded the Thiel Fellowship and helped create deep science fund Breakout Labs. Previously, he helped lead the U.S. Department of Health and Human Services as the principal associate deputy secretary, where he was responsible for overseeing policy and regulations at NIH, FDA, and CDC and led two major reforms of FDA. He supported the creation of the Armed Forces Institute for Regenerative Medicine, served on the steering committee of the Biomedical Advanced Research and Development Authority, and represented the United States on the U.S. delegation to the World Health Assembly. “Over the past decade, Mike and Aubrey built a team of scientists dedicated to damage repair and turned skeptics into advocates along the way,” said O’Neill. “The growing interest in technologies that can reverse aging is proof of their vision and determination. I’m excited to advance SRF’s vision to bring the benefits of such technologies to the public.”

“This is an historic moment for SENS Research Foundation,” said Dr. Aubrey de Grey, co-founder and Chief Science Officer of SRF. “Underdog may well become one of the most significant endeavors in the rejuvenation biotechnology industry, and Mike and Oki are the perfect team to make it a success. And with Jim’s deep experience in investment and policy, and Alex’s brilliance in research and teaching, I’ve no doubt our mission is in good hands. I’m delighted to have their leadership and expertise at SRF.”

About Underdog

Underdog Pharmaceuticals, Inc., is pursuing a mission to treat the underlying causes of age-related disease. The company develops simple and direct interventions targeting toxic forms of cholesterol using rationally designed molecules to provide the first true disease-modifying treatments for age-related diseases such as atherosclerosis, hypercholesterolemia, heart failure, and macular degeneration. Its products are based on novel derivatives of a well-known, safe compound and a new way of looking at cardiovascular disease created through a SENS Research Foundation program. For more information, please visit underdogpharma.com.

About SENS Research Foundation

SENS Research Foundation is a 501(c)(3) nonprofit that works to research, develop and promote comprehensive regenerative medicine solutions for the diseases of aging. SRF supports research projects focused on a damage repair paradigm at universities and institutes around the world with the goal of curing such age-related diseases as heart disease, cancer, and Alzheimer’s disease. SRF educates the public and trains researchers to support a growing regenerative medicine field through advocacy campaigns and educational programs. For more information, please visit sens.org.

About Kizoo

Kizoo provides mentoring and seed and early-stage financing with a focus on rejuvenation biotechnology. Having been entrepreneurs, VCs, and mentors in both high-growth tech and biotech companies for many years, with multiple exits and massive value created for the founders, Kizoo now brings this experience to the emerging field of rejuvenation biotech – a young industry that will eventually become much bigger than today’s largest technology markets.

As part of the Forever Healthy Group, Kizoo directly supports the creation of startups turning research on the root causes of aging into therapies and services for human application. Investments include AgeX, FoxBio, Turn.bio, Elevian, Oisin Biotechnologies, LIfT BioSiences, MAIA Biotechnology, and others. Forever Healthy’s other initiatives include the evaluation of new rejuvenation therapies, evidence-based curation of the world’s cutting-edge medical knowledge, funding research projects on the root causes of aging, and hosting the annual Undoing Aging Conference. For more information, please visit: kizoo.com and forever-healthy.org.

Notice:
This press release is not an offer to sell or a solicitation of an offer to buy securities in any jurisdiction. No securities commission or regulatory authority has approved or disapproved the information contained herein.

Media contacts:
For Underdog: [email protected]
For SRF: [email protected]
For Kizoo: [email protected]

Identification and Targeting of Noncanonical Death Resistant Cells

SENS Research Foundation Research Center

Forever Healthy Foundation Fellowship in Rejuvenation Biotechnology

Principal Investigator: Tesfahun Admasu / Alexandra Stolzing

When cells age, they lose their proliferative capacity and stop dividing in a phenomenon called senescence. Cellular senescence decreases the regenerative capacity of cells and tissues.

Throughout the aging process, senescent cells accumulate and secrete a characteristic set of proteins, called a senescence-associated secretory phenotype (SASP). Although SASPs act as tumor suppressors and recruit immune cells to repair damage, they also exacerbate the deleterious effects of senescence in the development of pathologies such as cancer, neurodegenerative diseases, and diabetes. Furthermore, SASPs can induce senescence in surrounding cells (called ‘secondary senescence’ or ‘paracrine senescence’), which can aggravate the effect. While primary senescent cells are fairly well characterized at this point, not much is known about secondary senescent cells and how they are arise in vivo.

Project Goals

This project seeks to confirm the hypothesis that secondary senescent cells are different from primary senescent cells, and would therefore need a different senolytic to eradicate them. In addition, the project will study how SASP components mediate the spread of senescence. This work could provide us with the basis for a new, therapeutically viable hypothesis for stopping the spread.

Job Opportunity: Research Assistant (Immunology)

SENS Research Foundation (SRF) is hiring a Research Assistant for our Research Center (RC) located in Mountain View, CA. SRF is an exciting, cutting edge non-profit dedicated to transforming the way the world researches and treats age-related disease.

We are seeking a Research Assistant in our Senescence Immunology group for a project geared toward developing therapeutic interventions to rejuvenate immune clearance of senescent cells. This project involves working with human blood samples and primary human cells. This is a full-time position.

Qualified candidates will have a BS or MS in the chemical/biological sciences and substantial bench experience. Duties will include mostly bench work in a small team-oriented environment.

Candidates should have experience in WBC purification, culturing primary cells, quantitative real-time PCR, western blot, immunofluorescence, ELISA, micro plate readers, FACS analysis, and data analysis. Candidates with experience in 2nd and 3rd generation lentivirus system are particularly encouraged to apply.

Interested candidates should submit a cover letter and resume to [email protected].

We offer an excellent benefits package including paid vacation and sick leave, fully covered health insurance (inclusive of dependents), an FSA program, and a company matched 401(k) plan, all of which is offered after a 90-day introductory period. SENS Research Foundation is an equal opportunity employer.

The position is available now and will be filled as soon as the qualified candidate is found. Salary is commensurate with job title.

Job Type: Full-time
Salary: $48,000 to $50,000/year

Question of the Month: Senolytics – Solution or Self-Defeating for Senescent Cells?

Q: When senolytic drugs cause senescent cells to die, other (younger) cells need to divide and take the place of the dead cells. This cell division causes telomere shortening, thus possibly creating new senescent cells. How is it that the process of killing senescent cells is not self-defeating if new senescent cells are being created?

There are a couple of ways to come at this question. The first is to just look at the astonishing beneficial effects of senolytic drugs or gene therapies in aging mice and mouse models of age-related disease.1,2 In these studies, senolytic drugs have restored exercise capacity1 and capacity to form new blood and immune precursor cells3 in aging mice to near youthful norms, while preventing age-related lung hypofunction,4 fatty infiltration into the liver,5 weakening or failure of the heart,1,6,7 osteoporosis,8 and hair loss.9 These treatments have also prevented or treated mouse models of diseases of aging like osteoarthritis,10 fibrotic lung disease,11,12 nonalcoholic fatty liver disease (NAFLD),5 atherosclerosis,13,14 cancer15 and the side-effects of conventional chemotherapy,2,16 as well as neurodegenerative diseases of aging like Parkinson’s17 and Alzheimer’s18,19,20 diseases… and on and on! So whatever collateral damage might ensue from ablating senescent cells, it’s pretty clear that senolytic treatments are doing a lot more good than harm.

But let’s drill down on the underlying reasoning of the question a little more. Suppose (as the question posits) that every time you destroy a senescent cell, a progenitor cell (one of the partly-specialized tissue-specific cells that repopulate a tissue with mature cells specific to that tissue) replicates to create a new cell to take its place. In fact, studies do show that when senescent cells are killed in a tissue, the progenitor cells begin to multiply and/or to function better as stem cells. This benefit is not due to the progenitor cells automatically replicating themselves and taking the place of the senescent cell, but because the baleful secretions spewed out of senescent cells inhibit the progenitor cells’ regenerative function, such that destroying senescent cells allows the progenitor cells to begin working properly again. This is observed in blood-cell-forming cells,3 cardiac progenitor cells,6 bone-forming cells,8 and the cells that form new fat cells — in both mice21 and now (in a small, short-term clinical trial) even in humans!22

So does this support the worry behind the question? Not really. It just takes a moment’s thought to realize that just one such replication can’t possibly be enough to drive a stem/progenitor cell into senescence: if it did, of course, senolytic therapies would fail to reduce the net burden of senescent cells. But studies clearly show that administering senolytics does lower the overall number of senescent cells in aging and diseased tissues.

Also, if these drugs were not killing more senescent cells than they indirectly produced, you wouldn’t get relief from the harmful effects of having a high burden of senescent cells — and, of course, you do, in multiple tissues and in multiple models of aging and age-related disease.

Going Back to the Well for More

Still, even if a single round of senolytics isn’t enough to drive your stem cells senescent, what if you turn one tissue stem cell senescent for every two times they are triggered to proliferate by senolytic therapy — or every three, or four, or ten? Might a single round of senolytic drugs be a net benefit, whereas repeated treatments over a lifetime would deplete tissue stem cells step by step, eventually riddling the body with senescent cells and leaving the patient (murine or human) worse off over the long term?

Fortunately, we have long-term studies to address that question — and they tell us again that the answer is “no.”

In a study that played a critical role in launching the senolytic drug revolution,15 mice were engineered with a genetic self-destruct mechanism built into all of their cells, which would lie dormant until activated by a two-part command: one, the expression of the gene p16, which is characteristic of senescent cells; and two, an activating drug that scientists could administer to control the pace of senolytic activity. The researchers then waited until the animals were 12 months old (in human terms, this is similar to a person in his or her early 40s) before administering the drug for the first time. They then continued administering the drug every two weeks for the next six months — at which point the animals had received thirteen rounds of senescent cell-clearing therapy, and were roughly similar to humans in their mid-fifties.15

The study clearly showed that the animals benefitted from senolytic therapy, even after undergoing round after round of treatment across the span of their natural middle age through to early natural seniority.15 For instance, the animals whose senescent cell autodestruct mechanism had been triggered subsequently retained more functioning filtering units in their kidneys with age, and fewer of them died in middle age and early seniority.15

More directly on point with our question, the researchers looked to see the effects of multiple rounds of senolytic therapy on total senescent cell burden, and whether they substantially depleted the animals’ reserves of functional progenitor cells by forcing them to divide their way into senescent doom.14 To do this, the investigators looked at the effects of treatment on the preadipocytes (the progenitor cells that form fat cells (adipocytes)) in the animals’ fat tissue — a convenient place to look, because it’s easy to get at, and because it accumulates substantial numbers of senescent cells with age.

After some 13 rounds of senolytic therapy, the treated animals had only one eighth the number of senescent preadipocytes as controls (Figure 1(a)) — a very substantial net reduction. Yet even so, the treated animals still had just as many functional progenitors left — or so close to as many that the difference was indistinguishable from chance (Figure 1(b)).15

Figure 1.

Activating senolytic “self-destruct” genes throughout midlife sustainably slashes senescent cell count (a) with no or very small effects on progenitor numbers (b) in adipose tissue. Bars in (b) with # are differences that were statistically significant. Redrawn from (15).

In another study,23 researchers administered the natural senolytic compound fisetin to mice every single day, starting from the point when they were already in early seniority (and thus already had both a large number of senescent cells, and a dwindling supply of progenitor cells) and continuing on until their death. The extended treatment slashed the number of senescent cells in most tissues in the order of 50%. On top of that, the animals lived substantially longer, and their tissues suffered less severe age-related degenerative lesions than control animals.23

Out with the Old - and In With the New

That said, it is important to have plenty of functional cells around in order to reap the full benefits of senolytic therapy. This was illustrated in a study using senolytic drugs or “self-destruct” genes to treat animal models of osteoarthritis.10 When joint disease was initiated by injury in young animals, the insult led to chronic joint damage and an accumulation of senescent cells in the synovium (the membrane surrounding the joint, where is the cells that maintain the complex fluid that lubricates the joint reside). Eliminating senescent cells reduced the inflammation in the joint, prevented joint erosion, and alleviated signs of pain in the animals.10

But senolytic treatment was much less effective when the scientists repeated the experiment in old animals, and the reasons why shed some light on our original question. Compared to young animals, the old animals accumulated many more senescent cells after their joints were injured, and those cells developed at deeper layers of the tissue, accompanied by more severe osteoarthritis.10 Perhaps this is because in the aging animals, more cells had already suffered significant aging damage, and were thus primed to be tipped over into senescence when injured. And when old animals were then administered senolytic treatment, the remaining healthy cells didn’t respond as well: the burden of zombie cells went down, and the old animals still got some pain relief, but genes that helped the young animals regenerate their damaged joints were not activated, and the cartilage quality score did not improve. The researchers suggest that this could be due to a decline in the number or functional capacity of the non-senescent cartilage-forming cells, driven by degenerative aging processes.10

Similarly, destroying senescent cells in aging mice reduced the excessive numbers of osteoclasts (cells that break down bone) that accumulate in aging bone, but did not restore the dwindling supply of bone-forming osteoblasts, lack of which no doubt constrained the rejuvenating effects of senolytic treatment in restoring the aging bone.8

In both of these cases, the lack of a boost to the number or activity of youthful cells was not the result of damage from the senolytic drug: the failing supply of such cells had already occurred before treatment was initiated. So the problem is not that senolytic therapies stop working or become counterproductive over time: rather, it’s that they only target one kind of aging damage, whereas aging drives disease and disability because of the accumulation of multiple kinds of cellular and molecular damage in our tissues with age. The solution is to pair the killing of senescent cells with the introduction of fresh, new functional cells via cell therapy. (See our analysis of a previous study on senolytic therapy in models of Parkinson’s disease for the clinical path ahead on such combination therapies).

And to return more directly to the original question, this would also be the solution if it ultimately turns out that many decades of of senolytic therapy really did drive too many tissue stem cells into senescence. But as we’ve seen, all the evidence suggests that this won’t be a problem during the decades of our current lifespans.

References

  1. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O’Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644-58. doi: 10.1111/acel.12344. Epub 2015 Apr 22. PubMed PMID: 25754370; PubMed Central PMCID: PMC4531078.
  2. Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell. 2017 Mar 23;169(1):132-147.e16. doi: 10.1016/j.cell.2017.02.031. PubMed PMID: 28340339; PubMed Central PMCID: PMC5556182.
  3. Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016 Jan;22(1):78-83. doi: 10.1038/nm.4010. Epub 2015 Dec 14. PubMed PMID: 26657143; PubMed Central PMCID: PMC4762215.
  4. Hashimoto M, Asai A, Kawagishi H, Mikawa R, Iwashita Y, Kanayama K, Sugimoto K, Sato T, Maruyama M, Sugimoto M. Elimination of p19(ARF)-expressing cells enhances pulmonary function in mice. JCI Insight. 2016 Aug 4;1(12):e87732. doi: 10.1172/jci.insight.87732. PubMed PMID: 27699227; PubMed Central PMCID: PMC5033852.
  5. Ogrodnik M, Miwa S, Tchkonia T, Tiniakos D, Wilson CL, Lahat A, Day CP, Burt A, Palmer A, Anstee QM, Grellscheid SN, Hoeijmakers JHJ, Barnhoorn S, Mann DA, Bird TG, Vermeij WP, Kirkland JL, Passos JF, von Zglinicki T, Jurk D. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun. 2017 Jun 13;8:15691. doi: 10.1038/ncomms15691. PubMed PMID: 28608850; PubMed Central PMCID: PMC5474745.
  6. Lewis-McDougall FC, Ruchaya PJ, Domenjo-Vila E, Shin Teoh T, Prata L, Cottle BJ, Clark JE, Punjabi PP, Awad W, Torella D, Tchkonia T, Kirkland JL, Ellison-Hughes GM. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell. 2019 Jun;18(3):e12931. doi: 10.1111/acel.12931. Epub 2019 Mar 10. PubMed PMID: 30854802; PubMed Central PMCID: PMC6516154.
  7. Anderson R, Lagnado A, Maggiorani D, Walaszczyk A, Dookun E, Chapman J, Birch J, Salmonowicz H, Ogrodnik M, Jurk D, Proctor C, Correia-Melo C, Victorelli S, Fielder E, Berlinguer-Palmini R, Owens A, Greaves LC, Kolsky KL, Parini A, Douin-Echinard V, LeBrasseur NK, Arthur HM, Tual-Chalot S, Schafer MJ, Roos CM, Miller JD, Robertson N, Mann J, Adams PD, Tchkonia T, Kirkland JL, Mialet-Perez J, Richardson GD, Passos JF. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 2019 Mar 1;38(5). pii: e100492. doi: 10.15252/embj.2018100492. Epub 2019 Feb 8. PubMed PMID: 30737259; PubMed Central PMCID: PMC6396144.
  8. Farr JN, Xu M, Weivoda MM, Monroe DG, Fraser DG, Onken JL, Negley BA, Sfeir JG, Ogrodnik MB, Hachfeld CM, LeBrasseur NK, Drake MT, Pignolo RJ, Pirtskhalava T, Tchkonia T, Oursler MJ, Kirkland JL, Khosla S. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med. 2017 Sep;23(9):1072-1079. doi: 10.1038/nm.4385. Epub 2017 Aug 21. Erratum in: Nat Med. 2017 Nov 7;23 (11):1384. PubMed PMID: 28825716; PubMed Central PMCID: PMC5657592.
  9. Yosef R, Pilpel N, Tokarsky-Amiel R, Biran A, Ovadya Y, Cohen S, Vadai E, Dassa L, Shahar E, Condiotti R, Ben-Porath I, Krizhanovsky V. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun. 2016 Apr 6;7:11190. doi: 10.1038/ncomms11190. PubMed PMID: 27048913; PubMed Central PMCID: PMC4823827.
  10. Jeon OH, Kim C, Laberge RM, Demaria M, Rathod S, Vasserot AP, Chung JW, Kim DH, Poon Y, David N, Baker DJ, van Deursen JM, Campisi J, Elisseeff JH. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017 Jun;23(6):775-781. doi: 10.1038/nm.4324. Epub 2017 Apr 24. PubMed PMID: 28436958; PubMed Central PMCID: PMC5785239.
  11. Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann-Stroissnigg H, Pirtskhalava T, Prakash YS, Tchkonia T, Robbins PD, Aubry MC, Passos JF, Kirkland JL, Tschumperlin DJ, Kita H, LeBrasseur NK. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017 Feb 23;8:14532. doi: 10.1038/ncomms14532. PubMed PMID: 28230051; PubMed Central PMCID: PMC5331226.
  12. Pan J, Li D, Xu Y, Zhang J, Wang Y, Chen M, Lin S, Huang L, Chung EJ, Citrin DE, Wang Y, Hauer-Jensen M, Zhou D, Meng A. Inhibition of Bcl-2/xl With ABT-263 Selectively Kills Senescent Type II Pneumocytes and Reverses Persistent Pulmonary Fibrosis Induced by Ionizing Radiation in Mice. Int J Radiat Oncol Biol Phys. 2017 Oct 1;99(2):353-361. doi: 10.1016/j.ijrobp.2017.02.216. Epub 2017 Mar 4. PubMed PMID: 28479002.
  13. Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, Hagler M, Jurk D, Smith LA, Casaclang-Verzosa G, Zhu Y, Schafer MJ, Tchkonia T, Kirkland JL, Miller JD. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016 Oct;15(5):973-7. doi: 10.1111/acel.12458. Epub 2016 Aug 5. PubMed PMID: 26864908; PubMed Central PMCID: PMC5013022.
  14. Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 2016 Oct 28;354(6311):472-477. Epub 2016 Oct 27. PubMed PMID: 27789842; PubMed Central PMCID: PMC5112585.
  15. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016 Feb 11;530(7589):184-9. doi: 10.1038/nature16932. Epub 2016 Feb 3. PubMed PMID: 26840489; PubMed Central PMCID: PMC4845101.
  16. Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, Koenig K, Le C, Mitin N, Deal AM, Alston S, Academia EC, Kilmarx S, Valdovinos A, Wang B, de Bruin A, Kennedy BK, Melov S, Zhou D, Sharpless NE, Muss H, Campisi J. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2017 Feb;7(2):165-176. doi: 10.1158/2159-8290.CD-16-0241. Epub 2016 Dec 15. PubMed PMID: 27979832; PubMed Central PMCID: PMC5296251.
  17. Chinta SJ, Woods G, Demaria M, Rane A, Zou Y, McQuade A, Rajagopalan S, Limbad C, Madden DT, Campisi J, Andersen JK. Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson’s Disease. Cell Rep. 2018 Jan 23;22(4):930-940. doi: 10.1016/j.celrep.2017.12.092. Epub 2018 Jan 28. PubMed PMID: 29386135; PubMed Central PMCID: PMC5806534.
  18. Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, Abdelmohsen K, Bohr VA, Misra Sen J, Gorospe M, Mattson MP. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci. 2019 May;22(5):719-728. doi: 10.1038/s41593-019-0372-9. Epub 2019 Apr 1. PubMed PMID: 30936558; PubMed Central PMCID: PMC6605052.
  19. Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature. 2018 Oct;562(7728):578-582. doi: 10.1038/s41586-018-0543-y. Epub 2018 Sep 19. PubMed PMID: 30232451; PubMed Central PMCID: PMC6206507.
  20. Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q, Orr ME. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell. 2018 Dec;17(6):e12840. doi: 10.1111/acel.12840. Epub 2018 Oct 11. PubMed PMID: 30126037; PubMed Central PMCID: PMC6260915.
  21. Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, Sepe A, Johnson KO, Stout MB, Giorgadze N, Jensen MD, LeBrasseur NK, Tchkonia T, Kirkland JL. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife. 2015 Dec 19;4:e12997. doi: 10.7554/eLife.12997. PubMed PMID: 26687007; PubMed Central PMCID: PMC4758946.
  22. Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL, Kellogg TA, Khosla S, Koerber DM, Lagnado AB, Lawson DK, LeBrasseur NK, Lerman LO, McDonald KM, McKenzie TJ, Passos JF, Pignolo RJ, Pirtskhalava T, Saadiq IM, Schaefer KK, Textor SC, Victorelli SG, Volkman TL, Xue A, Wentworth MA, Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019 Sep;47:446-456. doi: 10.1016/j.ebiom.2019.08.069. Epub 2019 Sep 18. PubMed PMID: 31542391.
  23. Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28. doi: 10.1016/j.ebiom.2018.09.015. Epub 2018 Sep 29. PubMed PMID: 30279143; PubMed Central PMCID: PMC6197652.

SRF Research Center Immunologist Application Form

UPDATE: This post has been filled.

Immunologist

SENS Research Foundation (SRF) is seeking a full-time researcher for a Scientist position to work at our Research Center located in Mountain View, California. The position is to lead a new intramural research project geared toward performing translational research studying aging as it relates to the immune system, with a possibility of developing a new therapeutic. This is a collaborative effort between SRF and the Campisi Lab at the Buck Institute for Research on Aging, located in Novato, CA. The collaboration allows the researcher to work with two institutions at the forefront of the anti-aging field, and allow for mentorship from experts in the field. The successful applicant will work with, and be guided by, senior researchers at both SRF and the Buck, and as such this position is available to new PhDs as an alternative to doing a Postdoc (or a 2nd postdoc). The position offers the opportunity for upward mobility into a more senior, PI level position. Leading a team at SRF is an exciting career opportunity in a team environment where everyone is dedicated to discovering new treatments for the diseases and disabilities of aging.

Required Experience

  • PhD or equivalent doctoral degree in the chemical/biological sciences
  • Expertise in the innate immune system

Desired Capabilities

  • Independent planning and project design
  • NK cell knowledge or experience
  • Proficient at the bench and with data analysis
  • Management / mentoring experience
  • Comfortable working in a small team environment and with collaborations with other institutions

Compensation

SRF is proud to offer a competitive salary of $65-75,000/yr for this position, which includes paid vacation and sick leave, fully covered health insurance, inclusive of dependents, an FSA program, and a company matched 401(k) plan offered after a 90-day introductory period. SRF is an equal opportunity employer.

Interested candidates should apply by email to Dr. Matthew O’Connor, taking care to include all of the information and documentation listed below.

Applicants moving onto the second phase of the application process will be contacted by email by a SRF representative for an interview.

Application Information

Contact Information:

  • Last Name / Surname
  • First Name / Given Name
  • Email Address
  • Phone Number
  • Full Mailing Address

Academic Information:

  • Graduate Institution
  • Program or Department
  • Graduation Date
  • First available date to begin position

Documents:

Attach documents in PDF, DOC or DOCX format.

  • CV or Resume.  Please limit your CV or resume to a maximum of 2 pages. Highlight any prior laboratory or research experience. A brief 1- or 2-line description of your specific contribution to each research project is particularly helpful. For instance, the statement “created the expression construct that allowed us to determine protein localization” quickly clarifies your role in the project.
  • Cover Letter.  A cover letter describing your knowledge of SRF’s damage repair approach to aging as well as your experience in immunology; please limit your letter to one page.

A Small Molecule Approach to Removal of Toxic Oxysterols as a Treatment For Atherosclerosis

This research program has successfully spun-out into a company! Visit the Underdog Pharmaceuticals, Inc. website for more information on their transformative approach to atherosclerosis.

SENS Research Foundation Research Center

Principal Investigator: Matthew O’Connor
Research TeamAmelia Anderson, Carolyn Barnes, Angielyn Campo, Anne Corwin, Sirish Narayanan

Many diseases of aging are driven in part by the accumulation of “junk inside cells:” stubborn, damaged waste products derived from the metabolic processes particular to specific cell types. The accumulation of these wastes disables the cell type in question and leads to their dysfunction; when, after decades of silent accrual, a critical number of these cells become dysfunctional, diseases of aging characteristic of that tissue erupt. For example, atherosclerotic lesions form when immune cells called macrophages take in 7-ketocholesterol (7-KC) and other damaged cholesterol byproducts in an effort to protect the arterial wall from their toxicity, only to ultimately fall prey to that same toxicity themselves. These macrophages – now dysfunctional “foam cells” – become immobilized in the arterial wall and spew off inflammatory molecules that in turn promote advanced atherosclerosis, heart attack, and stroke. In other organs, the accumulation of damaged molecules inside vulnerable cells drives Alzheimer’s and Parkinson’s diseases, as well as age-related macular degeneration.

Dr. O’Connor’s team have identified a family of small molecules that may be able to selectively remove toxic forms of cholesterol from early foam cells and other cells in the blood. If effective, these small molecules could serve as the basis for a groundbreaking therapy that would prevent and potentially reverse atherosclerosis and, possibly, heart failure.

Research Highlights:

A lead compound was identified following evaluation of data from human blood sample tests in conjunction with computer modeling to predict the likely behavior of rationally-designed molecules. Preliminary testing has indicated performance consistent with enhanced activity relative to the existing family of compounds: specifically, the candidate molecules exhibit selective targeting of toxic cholesterol byproducts, with significantly reduced affinity for native cholesterol. A patent application for this lead compound and others to be derived from it has now been submitted.

The team is now working to refine their original assay with the expectation that it will more accurately reflect the desired activity on toxic and native cholesterol, and also on an entirely different chemical approach to improved molecules derived from the original family. We are also working with a potential contract laboratory to test the absorption, circulation to tissues, and disposal of our lead candidate, and to perform toxicity assays. SRF has recently acquired a new robotic system to run the assay, which our in-house engineer, Anne Corwin, is now working to set up and program; the end result will be an increase in throughput that allows more rapid testing of more molecules.

Engineering New Mitochondrial Genes to Restore Mitochondrial Function (MitoSENS)

SENS Research Foundation Research Center

Principal Investigator: Amutha Boominathan
Research Team: Nana Abena Anti, David Begelman, Bhavna Dixit, Caitlin Lewis, Sanjana Saravanan

Mitochondria are the tiny cellular “power plants” in our cells, which take energy from our food and convert it into a form that can be used to power the cell’s energy-intensive processes. Unfortunately, like actual power plants, they generate waste – in this case called free radicals, which damage mitochondrial DNA (mtDNA) over time. As a result, some cells become burdened by these dysfunctional mitochondria and can accumulate in the body as we age. These damaged cells in turn export toxic molecules to far-flung tissues, contributing to Parkinson’s disease, age-related muscle dysfunction, and other conditions.

The MitoSENS goal is to engineer a solution to the accumulation of cells with these mutation-bearing mitochondria via allotopic expression.  Allotopic expression involves placing “backup copies” of all the protein-coding genes of the mtDNA in the cell’s nucleus. From this “safe harbor,” the copied genes can then direct the cell’s machinery to produce engineered versions of the missing mitochondrial proteins and deliver them to the correct location. With their full complement of proteins restored, mitochondria can resume producing energy normally – despite lacking functional copies of these genes to produce them on their own.

Research Highlights:

In 2019, the MitoSENS team achieved a major breakthrough in successfully demonstrating transient allotopic expression for all 13 mtDNA genes. This work was recently published in Redox Biology, 30 (2020) 101429. Several of these genes can be expressed stably and the team was further able to demonstrate a functional utility for these exogenous proteins in rescuing patient cell lines with specific mutations in the mtDNA genes ATP8, ATP6, and ND1 (Nucleic Acids Res. 44(19) 2016; 9342-9357 and Redox Biology 30 (2020) 101429).  

Our current efforts are focused on validating this strategy in rescuing some of the more common inherited disease conditions observed as a result of mutations to mtDNA, such as Leber’s Hereditary Optic Neuropathy (LHON) and Leigh’s syndrome. We are also exploring alternative strategies and software based prediction models to optimize the expression of all 13 mtDNA genes and the transport and integration of their corresponding proteins into the mitochondria.

The MitoSENS team also has ongoing experiments to demonstrate efficacy in living, breathing mice – specifically,  a transgenic ATP8 mouse derived from the Maximally Modifiable Mice (MMM) created through the SENS Research Foundation-funded work at Applied StemCell. The new MMM-derived mouse model will have the allotopic ATP8 copy engineered into their nuclear genomes but will inherit functionally compromised mitochondria (and thus mitochondrial DNA) from a cross with FVB mice, which have a specific mutation in the mitochondrial ATP8 gene. This work is being done in collaboration with the Brand lab at the Buck Institute and will include biochemical and behavioral assays to evaluate if the allotopically expressed ATP8 gene can rescue the phenotype.

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