Research Roundup: Gene Regulation and Longevity, Comparing COVID-19 Vaccines

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As the expression goes, "You can try to live forever or die trying." Why we age isn't well understood and seems to be involved with many different molecular processes, including cell senescence and telomere length. Now, researchers have added another piece to the puzzle, finding how two gene regulatory systems are critical to regulating lifespan. For that story, as well as a head-to-head comparison of four COVID-19 vaccines and more, continue reading.

Gene Regulation and Longevity

Researchers at the University of Rochester found specific characteristics of genes that appear to regulate lifespan. They involve two regulatory systems, circadian and pluripotency networks. Both are critical to longevity. They compared the gene expression patterns of 26 mammalian species whose lifespans vary significantly, from shrews for two years and naked mole rats of 41 years. They identified thousands of genes associated with each species' maximum lifespan that either positively or negatively affected longevity. They published their research in the journal Cell Metabolism.

"To live longer, we have to maintain healthy sleep schedules and avoid exposure to light at night as it may increase the expression of the negative lifespan genes," Vera Gorbunova, Ph.D., the Doris Johns Cherry Professor of biology and medicine, said.

Their research found that the species that lived the longest have the lowest expression of genes involved in energy metabolism and inflammation. They also had high expression of genes involved in DNA repair, RNA transport, and organization of the cellular skeleton (microtubules). Earlier research suggested that mammals with long lifespans had more efficient DNA repair and a weaker inflammatory response, but the opposite was true of short-lived species. The negative lifespan genes are involved in energy metabolism, inflammation, and circadian networks. These can be influenced at least somewhat by sleep and light exposure. But the positive lifespan genes, such as those involved in DNA repair, RNA transport and microtubules, are controlled by the pluripotency network, which is involved in reprogramming somatic cells.

Head-to-Head Comparison of 3 Types of COVID-19 Vaccines

La Jolla Institute for Immunology investigators conducted a head-to-head comparison of four different COVID-19 vaccines with three different types of technologies to determine how they primed the immune system differently. They evaluated an mRNA platform (Pfizer-BioNTech and Moderna vaccines), a recombinant protein-based adjuvanted vaccine platform (Novavax) and a viral vector-based platform (Janssen/Johnson & Johnson). They found that the Moderna shot produced the highest levels of neutralizing antibodies, followed by the Pfizer-BioNTech and Novavax vaccines. The J&J vaccine created the lowest neutralizing antibody levels and made the highest percentage of memory B cells after six months. All vaccines generated a similar percentage of memory CD4+ "helper" T cells. The Novavax vaccine developed the lowest levels of CD8+ "killer" T cells, with the best given to Pfizer-BioNTech, Moderna, or J&J, although only 60% to 70% after six months of participants retained memory CD8+ T cells.

The bottom line appears to be that although it can be hard to maintain a high level of neutralizing antibodies over the long term, the stable cellular immunity suggests the immune system can be reactivated quickly if there is an infection, often in a matter of days.

New Type of Brain Cell Discovered Associated with Memory Formation

The hippocampus is the part of the brain that plays a major role in learning and memory. Scientists at Aarhus University in Denmark discovered a novel neuron type in the hippocampus. A sharp wave ripple (SWR) is a brief, high-frequency electrical event created in the hippocampus and is thought to be associated with episodic memory, or memories in an individual's life, such as childhood memories. Working with mice, they found a new type of neuron that is maximally active during SWRs when the mice were awake, quiet or deeply asleep. But it is not active at all when slow, synchronized neuronal population activity known as "theta" can occur in an awake animal or during dreaming. The new neuron is called theta off-ripples on (TORO). TOROs are activated by other types of hippocampus neurons, primarily CA3 pyramidal-neurons; they are also inhibited by inputs coming from other parts of the brain. TOROs are inhibitory neurons that release the neurotransmitter GABA within the hippocampus and send them to other brain areas outside the hippocampus, such as the septum and cortex. This appears to be a way of signaling to the rest of the brain that a memory event occurred.

Ultrasound-Guided Microbubbles to Improve Immuno-Oncology

Researchers at The University of Texas MD Anderson Cancer Center developed a cancer immunotherapy platform that uses ultrasound to guide nanocomplexes combined with microbubbles. This platform effectively delivered cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) into antigen-presenting cells (APCs). Once inside the APCs, the microbubbles released cGAMP, an immunotransmitter involved in anticancer immunity. cGAMP activates the GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway. This in turn, stimulates type I interferon response essential for promising tumor-specific T cells. The strategy, dubbed MUSIC, completely eradicated 60% of tumors when administered as a monotherapy in breast cancer models in preclinical assays. When dosed with an anti-PD-1 checkpoint inhibitor, MUSIC significantly improved antitumor responses, with superior survival benefit with a 76% increase in median survival compared to either therapy alone.

Your Liver Is Still a Toddler

The human liver has an unusual and unique ability to regenerate after damage. Researchers at the Technische Universit├Ąt Dresden wanted to determine if this ability decreases with age. Using a technique called retrospective radiocarbon birth dating, they found they could identify the age of the human liver. And they found that no matter how old you are, your liver is always slightly less, on average, than three years old. The research indicated that aging doesn't influence liver regeneration. This healing and regrowth ability appears related to the liver's primary function, clearing toxins, which likely causes regular injury. They analyzed the livers of people between the ages of 20 and 84 years and found that overall the liver cells were approximately the same age.

"No matter if you are 20 or 84, your liver stays on average just under three years old," said Olaf Bergmann, Ph.D., research group leader at the Center for Regenerative Therapies Dresden (CRTD) at TU Dresden.

Not all liver cells stay that young. Some can live up to 10 years before going through renewal, and this subpopulation of cells carries more DNA than typical cells. They discovered fundamental differences between the amount of DNA in older cells compared to more normal younger cells.

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