Lifeboat Foundation

We’re continuing to release talks from Ending Age-Related Diseases 2019, our highly successful two-day conference that featured talks from leading researchers and investors, bringing them together to discuss the future of aging and rejuvenation biotechnology.

In his talk, The Reversal of the Aging of Human Cells: Strategies for Clinical Implementation, Dr. West discussed the differences between germ-line and somatic cells, embryonic regeneration in humans, organisms that do not age, the Weismann Barrier, the ways in which cellular immortality is repressed in human beings (somatic restriction), cellular reprogramming, and how AgeX is attempting to create stem cell populations for regenerative therapies.

“Everyone is searching for a magic pill that will cure ageing,” explains Richard Siow, who heads up ageing research at King’s College London. “The truth is, lifestyle and diet changes are the most realistic way to extend your life. You can’t just adopt these as you get older. You need to start young – we’re ageing from the moment we’re born.”

Of course, diet and exercise alone won’t enable humans to achieve immortality. We profile the scientists and startups trying to hold back time.

Growing evidence supports the antagonistic pleiotropy theory of mammalian aging. Accordingly, changes in gene expression following the pluripotency transition, and subsequent transitions such as the embryonic–fetal transition, while providing tumor suppressive and antiviral survival benefits also result in a loss of regenerative potential leading to age-related fibrosis and degenerative diseases. However, reprogramming somatic cells to pluripotency demonstrates the possibility of restoring telomerase and embryonic regeneration pathways and thus reversing the age-related decline in regenerative capacity. A unified model of aging and loss of regenerative potential is emerging that may ultimately be translated into new therapeutic approaches for establishing induced tissue regeneration and modulation of the embryo-onco phenotype of cancer.

Keywords:

• acetyl-CoA
• aging
• AMPK
• dietary restriction
• DNA methylation
• epigenetics
• mTOR
• pluripotent stem cells
• regeneration

Aging is often defined as a progressive deterioration of an organism over time, wherein the risk of mortality increases exponentially with age in the postreproductive years. Although everyday environmental risks from predation or infectious disease (e.g., stochastic risks) necessarily lead to increased mortality over time, they are not considered core to the definition of the aging process per se [1,2]. Thus, an important criterion of aging is that it encompasses virtually every somatic tissue type, including the gonads (though not necessarily the germ-line cells themselves, given their role in potentially perpetuating the species) [3]. In order to distinguish the aging process from damage that occurs stochastically over time, Benjamin Gompertz described aging as a process leading to an exponential increase in mortality with time, that is, R_m = R₀e^at where ‘R_m’ represents the probability of mortality between ages ‘t’ and ‘t + 1’.

Taken from JRE #1349 w/David Sinclair:

Researchers at Mayo Clinic have identified the enzyme, called CD38, that is responsible for the decrease in nicotinamide adenine dinucleotide (NAD) during aging, a process that is associated with age-related metabolic decline. Results demonstrated an increase in the presence of CD38 with aging in both mice and humans. The results appear today in Cell Metabolism.

“As we age, we experience a decline in our metabolism and metabolic function. This increases the incidence of age-related metabolic diseases like obesity, diabetes and others,” says Eduardo Chini, M.D., Ph.D., anesthesiologist and researcher for Mayo Clinic’s Robert and Arlene Kogod Center on Aging and lead author of the study. “Previous studies have shown that levels of NAD decline during the aging process in several organisms. This decrease in NAD appears to be, at least in part, responsible for age-related metabolic decline.”

In this study, researchers at the Center on Aging have shown that CD38, an enzyme that is present in inflammatory cells, is directly involved in the process that mediates the age-related NAD decline. Comparing 3- to 32-month-old mice, researchers found that levels of CD38 increased at least two to three times during chronological aging in all tissues tested, including the liver, fat, spleen and skeletal muscle.

Dr. David Sinclair, a Professor of Genetics at Harvard Medical School, is one of the most well-known researchers in the field of rejuvenation, and his lab is the beneficiary of a successful Lifespan.io campaign.

Today, Dr. Sinclair is releasing his book on Amazon, “Lifespan: Why We Age and Why We Don’t Have To”, and on Wednesday, September 18, we will be hosting a webinar with Dr. Sinclair as well. Please contact [email protected] if you would like to join or have any questions regarding this webinar.

At International Perspectives in Geroscience, a conference hosted at Weizmann Institute of Science (Israel) on September 4–5, we had the opportunity to interview Dr. Sinclair about his work and his thoughts on the current state of research.

Bioengineers and life scientists incorporate hybridoma technology to produce large numbers of identical antibodies, and develop new antibody therapeutics and diagnostics. Recent preclinical and clinical studies on the technology highlight the importance of antibody isotypes for therapeutic efficacy. In a new study, a research team in Netherlands have developed a versatile Clustered Regularly Interspaced Short Palindrome Repeats (CRISPR) and homology directed repair (HDR) platform to rapidly engineer immunoglobin domains and form recombinant hybridomas that secrete designer antibodies of a preferred format, species or isotype. In the study, Johan M. S. van der Schoot and colleagues at the interdisciplinary departments of immunology, proteomics, immunohematology, translational immunology and medical oncology, used the platform to form recombinant hybridomas, chimeras and mutants. The stable antibody products retained their antigen specificity. The research team believes the versatile platform will facilitate mass-scale antibody engineering for the scientific community to empower preclinical antibody research. The work is now published on Science Advances.

Monoclonal antibodies (mAb) have revolutionized the medical field with applications to treat diseases that were once deemed incurable. Hybridoma technology is widely used since 1975 for mAb discovery, screening and production, as immortal cell lines that can produce large quantities of mAbs for new antibody-based therapies. Scientists had generated, validated and facilitated a large number of hybridomas in the past decade for preclinical research, where the mAb format and isotypes were important to understand their performance in preclinical models. Genetically engineered mAbs are typically produced with recombinant technology, where the variable domains should be sequenced, cloned into plasmids and expressed in transient systems. These processes are time-consuming, challenging and expensive, leading to outsourced work at contract research companies, which hamper the process of academic early-stage antibody development and preclinical research.

In its mechanism of action, the constant antibody domains forming the fragment crystallizable – (Fc) domain are central to the therapeutic efficacy of mAbs since they engage with specific Fc receptors (FcRs). Preceding research work had highlighted the central role of Fc in antibody-based therapeutics to emphasize this role. Since its advent, CRISPR and associated protein Cas-9 (CRISPR-Cas9)-targeted genome editing technology has opened multitudes of exciting opportunities for gene therapy, immunotherapy and bioengineering. Researchers had used CRISPR-Cas9 to modulate mAb expression in hybridomas, generate a hybridoma platform and engineer hybridomas to introduce antibody modification. However, a platform for versatile and effective Fc substitution from foreign species within hybridomas with constant domains remains to be genetically engineered.