How brain cells repair their DNA reveals “hot spots” of aging and disease

Good news! Possibly a breakthrough! This is probably some critical research!

"... Now, a new study by Salk scientists finds that these repairs are not random, but instead focus on protecting certain genetic “hot spots” that appear to play a critical role in neural identity and function. ...
“This research shows for the first time that there are sections of genome that neurons prioritize when it comes to repair,” ... “We’re excited about the potential of these findings to change the way we view many age-related diseases of the nervous system and potentially explore DNA repair as a therapeutic approach.” ...
The authors found approximately 65,000 hot spots that covered around 2 percent of the neuronal genome. They then used proteomics approaches to detect what proteins were found at these hot spots ...
Previous research has focused on identifying the sections of DNA that suffer genetic damage, but this is the first time researchers have looked for where the genome is being heavily repaired. ..."

"Humans have only a limited capacity to generate new neurons. These cells thus need to repair errors in the genome. To better understand this process, [researchers] developed Repair-seq, a method to locate DNA repair within the genome of stem cell–derived neurons. DNA repair hotspots (DRHs) were more likely to occur within specific genomic features such as gene bodies as well as in genomic formations, open chromatin, and active regulatory regions. This method showed that repair was enriched at sites involved in neuronal function and identity. Furthermore, proteomic data indicated that genes in DRHs are enriched in Alzheimer's disease and that DRHs are more active in aging. ..."

"Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell–induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system."

How brain cells repair their DNA reveals “hot spots” of aging and disease - Salk Institute for Biological Studies Salk scientists reveal new insights into neurodegenerative disorders and potential for genetic therapies

Here is the link to the underlying research article:

Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons (no public access)

Closing In On The Fountain Of Youth

Posted: 4/1/2017  Updated: 11/16/2017, 4/16/2017

Update Of 11/16/2017

Just read Scientists decipher mechanisms underlying the biology of aging Multi-pronged approach reveals a delicate balance required for longevity:

“Cells periodically switch between "on" and "off" in their chromatin state during aging. Aged cells lose this switching capability, resulting in cell death. These findings uncover a potential cause of cellular aging and suggest new ways to promote longevity.” (emphasis added)

Update Of 4/16/2017

The quest continues and yields new scientifically based discoveries: A fishy way to longevity: young poo. If we are told to eat more insects to save the planet, why not eat young fish feces for longevity? :-) And this was published by Science News of the AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE .

The Myth Is Old

Humans have been dreaming about a fountain of youth for millennia. “My kingdom for a [longer life]” not a horse as Shakespeare would have it in the Richard III play! Many things have been tried, like the first emperor of China and his believe in mercury as the elixir of immortality.

Constantly, we learn about new findings regarding this myth. Lately, it was a substance found in red wine, i.e. resveratrol. Then there was caloric restriction diet or the shortening of telomeres with ageing. Or how about replacing your old blood with the blood of a younger person?

Trigger

At least three recent articles that I read lead me to believe that it would be possible within the next 10-20 years to dramatically slow down the biological ageing process in humans. Myth becomes reality or so it seems.

Confidence Comes With Knowledge

Here are the three articles, excerpts and comments (emphasis added):

1. Critical step found in DNA repair, cellular aging  Experiments in mice suggest way to thwart DNA damage from aging, radiation
   “.... The findings, to be published March 24 in Science, offer a critical insight into how and why the body’s ability to fix DNA dwindles over time and point to a previously unknown role for the signaling molecule NAD as a key regulator of protein-to-protein interactions in DNA repair. … Additionally, experiments conducted in mice show that treatment with the NAD precursor NMN mitigates age-related DNA damage and wards off DNA damage from radiation exposure. … the team homed in on a region of DBC1 known as NHD, a pocket-like structure found in some 80,000 proteins across life forms and species whose function has eluded scientists. The team’s experiments showed that NHD is an NAD binding site and that in DBC1, NAD blocks this specific region to prevent DBC1 from locking in with PARP1 and interfering with DNA repair. … that since NHD is so common across species, the finding suggests that by binding to it, NAD may play a similar role averting harmful protein interactions across many species to control DNA repair and other cell survival processes. … After receiving NMN with their drinking water for a week, however, old mice showed marked differences both in NAD levels and PARP1 activity. NAD levels in the livers of old mice shot up to levels similar to those seen in younger mice. The cells of mice treated with NMN also showed increased PARP1 activity and fewer PARP1 and DBC1 molecules binding together. The animals also showed a decline in molecular markers that signal DNA damage. ”
   [This sounds very promising! If we can find ways to improve DNA repair in our bodies, then this should be a huge advance!]
2. Molecule kills elderly cells, reduces signs of aging in mice
   “... frail and damaged cells that age us and promote disease. Now, researchers have developed a molecule that selectively destroys these so-called senescent cells. … Senescent cells carry the type of DNA damage that should spur a protective protein, called p53, to put them down. Instead, the researchers found that a different protein, FOXO4, latches onto p53 and prevents it from doing its duty. To counteract this effect, … designed a molecule, known as a peptide, that carries a shortened version of the segment of FOXO4 that attaches to p53. In a petri dish, this peptide prevented FOXO4 and p53 from hooking up, prompting senescent cells to commit suicide. But it spared healthy cells. The researchers then injected the molecule into mutant mice that age rapidly. ... However, the peptide boosted the density of their fur, reversed the kidney damage, and increased the amount of time they could scurry in a running wheel … When the researchers tested the molecule in normal, elderly mice, they saw a similar picture: In addition to helping their kidneys and fur, the molecule also increased their willingness to explore their surroundings. …  however, that [such] peptides … have their own limitations. The digestive system destroys them, so they can only be delivered through inhalation or an injection–you can’t just swallow a pill ...”
   [Getting rid of senescent cells could be very promising as well!]
3. Protein Hints at a Fountain of Youth in Blood  It’s another tantalizing finding in an area of anti-aging research that has had mixed results.
   “... The compound makes old mice act and appear more youthful … that older mice had low levels of a protein called osteopontin, and that stem cells injected into the mice quickly aged. The reverse—putting old stem cells into a dish filled with osteopontin—appeared to rejuvenate them. …”
   [There is almost always more than one way to achieve a goal!]

If we can combine those discoveries, then the fountain of youth