Lifeboat Foundation: Safeguarding Humanity
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Category: genetics

David Sinclair is a geneticist at Harvard and author of Lifespan.

Nature – Reversal of biological clock restores vision in old mice

Sinclair and his team restored vision in old mice and in mice with damaged retinal nerves by resetting some of the thousands of chemical marks that accumulate on DNA as cells age. They are now working to rejuvenate the brains of old mice. This work is so promising that Sinclair believes he can get to human trials within two years. Sinclair is using three genes to reset the age of cells.

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New research suggests age-related changes in blood cell chromosomes are a marker of impaired immunity.

A person’s risk of severe infections increases dramatically as they grow older, but scientists do not yet understand how age might be linked to weakened immunity. Now, research shows that certain age-related changes in are associated with a higher risk of a range of severe infections including severe COVID-19, other pneumonias, and sepsis.

Researchers analyzed genetic and clinical data from nearly 800000 patients from around the world. They discovered that people with a specific type of acquired rearrangement in the chromosomes of their cells, called mosaic chromosomal alterations (mCAs), were nearly three times more likely to develop sepsis and two times more likely to get pneumonia than those without mCAs. These genetic changes accumulate in blood cells with age and often indicate a common condition in the elderly called clonal hematopoiesis.

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~Fun Sunday Links~

*See comments section*

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For all the cool regenerative tricks the human body can do, it’s kind of weird that we only have one shot at tooth enamel with no way to get it back. That may be about to change, as researchers at the University of Washington have developed a lozenge that rebuilds this precious protective coating a few microns at a time and are taking it to the trial stage. Could it really work? It’s certainly something to chew on.

The lozenge uses a genetically-engineered peptide (a chain of amino acids) derived from a protein that’s involved in developing enamel in the first place, as well as with the formation of the root surface of teeth. Inside the lozenge, this peptide works alongside phosphorus and calcium ions, which are the building blocks of tooth enamel. It’s designed to bind to damaged enamel without harming the gums, tongue, or other soft tissues of the mouth.

The researchers have already verified the efficacy on teeth extracted from humans, pigs, and rats, so the trials will largely revolve around comparing it to other whitening methods and documenting their findings.

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Don’t worry you haven’t stumbled onto that strange part of the internet again, but it is true that we never truly did sequence the entire Human genome. For you see what was completed in June 2000 was the so called ‘first draft’, which constituted roughly 92% of genome. The problem with the remaining 8% was that these were genomic ‘dead zones’, made up of vast regions of repeating patterns of nucleotide bases that made studying these regions of the genome effectively impossible with the technology that was available at the time.

However, recent breakthroughs in high throughput nanopore sequencing technology have allowed for these so call dead zones to be sequences. Analysing these zone revealed 80 different genes which had been missed during the initial draft of the Human genome. Admittedly this is not many considering that the other 92% of the genome contain 19889 genes, but it may turn out that these genes hold great significance, as there are still many biological pathways which we do not fully understand. It is likely that many of these genes will soon be linked with what are known as orphan enzymes, which are proteins that are created from an unidentified gene, which is turn opens up the door to studying these enzymes more closely via controlling their expression.

So how does this discovery effect the field of regenerative medicine? Well the discovery of these hidden genes is potentially very significant for our general understand of Human biology, which in turn is important for our understanding of how we might go about fixing issues which arise. Possibly more important that the discovery of these hidden genes, is the milestone this sequencing represents in our ability to study our genomes quickly and efficiently with an all-inclusive approach. The vast amount of data that will soon be produced via full genome analysis will go a long way towards understanding the role that genetics play in keeping our bodies healthy, which in turn will allow us to replicate and improve upon natural regenerative and repair mechanisms. It might even allow us to come up with some novel approaches which have no basis in nature.

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Papers referenced in the video:

Sirtuins, Healthspan, and Longevity in Mammals.
https://www.sciencedirect.com/science/article/pii/B9780124115965000034

Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH
https://pubmed.ncbi.nlm.nih.gov/24011076/

Resveratrol improves health and survival of mice on a high-calorie diet.
https://pubmed.ncbi.nlm.nih.gov/17086191/

Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice.
https://pubmed.ncbi.nlm.nih.gov/20974732/

Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer.
https://www.nature.com/articles/ncomms1001

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The latest from Calico. A bit technical.

Reprogramming of ordinary somatic cells into induced pluripotent stem cells (iPSCs) was initially thought to be a way to obtain all of the patient matched cells needed for tissue engineering or cell therapies. A great deal of work has gone towards realizing that goal over the past fifteen years or so; the research community isn’t there yet, but meaningful progress has taken place. Of late, another line of work has emerged, in that it might be possible to use partial reprogramming as a basis for therapy, delivering reprogramming factors into animals and humans in order to improve tissue function, without turning large numbers of somatic cells into iPSCs and thus risking cancer or loss of tissue structure and function.

Reprogramming triggers some of the same mechanisms of rejuvenation that operate in the developing embryo, removing epigenetic marks characteristic of aged tissues, and restoring youthful mitochondrial function. It cannot do much for forms of damage such as mutations to nuclear DNA or buildup of resilient metabolic waste, but the present feeling is there is nonetheless enough of a potential benefit to make it worth developing this approach to treatments for aging. Some groups have shown that partial reprogramming — via transient expression of reprogramming factors — can reverse functional losses in cells from aged tissues without making those cells lose their differentiated type. But this is a complicated business. Tissues are made up of many cell types, all of which can need subtly different approaches to safe reprogramming.

Today’s open access preprint is illustrative of the amount of work that lies ahead when it comes to the exploration of in vivo reprogramming. Different cell types behave quite differently, will require different recipes and approaches to reprogramming, different times of exposure, and so forth. It makes it very hard to envisage a near term therapy that operates much like present day gene therapies, meaning one vector and one cargo, as most tissues are comprised of many different cell types all mixed in together. On the other hand, the evidence to date, including that in the paper here, suggests that there are ways to create the desired rejuvenation of epigenetic patterns and mitochondrial function without the risk of somatic cells dedifferentiating into stem cells.

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Critical advances in the investigation of brain functions and treatment of brain disorders are hindered by our inability to selectively target neurons in a noninvasive manner in the deep brain.

This study aimed to develop sonothermogenetics for noninvasive, deep-penetrating, and cell-type-specific neuromodulation by combining a thermosensitive ion channel TRPV1 with focused ultrasound (FUS)-induced brief, non-noxious thermal effect.

The sensitivity of TRPV1 to FUS sonication was evaluated in vitro. It was followed by in vivo assessment of sonothermogenetics in the activation of genetically defined neurons in the mouse brain by two-photon calcium imaging. Behavioral response evoked by sonothermogenetic stimulation at a deep brain target was recorded in freely moving mice. Immunohistochemistry staining of ex vivo brain slices was performed to evaluate the safety of FUS sonication.

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The idea is simple: decades of research have found certain genes that seem to increase the chance of Alzheimer’s and other dementias. The numbers range over hundreds. Figuring out how each connects or influences another—if at all—takes years of research in individual labs. What if scientists unite, tap into a shared resource, and collectively solve the case of why Alzheimer’s occurs in the first place?

The initiative’s secret weapon is induced pluripotent stem cells, or iPSCs. Similar to most stem cells, they have the ability to transform into anything—a cellular genie, if you will. iPSCs are reborn from regular adult cells, such as skin cells. When transformed into a brain cell, however, they carry the original genes of their donor, meaning that they harbor the original person’s genetic legacy—for example, his or her chance of developing Alzheimer’s in the first place. What if we introduce Alzheimer’s-related genes into these reborn stem cells, and watch how they behave?

By studying these iPSCs, we might be able to follow clues that lead to the genetic causes of Alzheimer’s and other dementias—paving the road for gene therapies to nip them in the bud.

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