Are you becoming forgetful in your old age? Don’t bother to reply, we know the answer and Prevagen isn’t it. Your friends all try to reassure you it’s just a common malady but that doesn’t help when you go to bed in Cleveland and somehow wake up in Detroit. “I was just driving down the street the other day,” said local agronomist Charles LeMasters, “and I had to pull over. I suddenly didn’t know where I was. Oddly enough, I wasn’t even stoned. Good thing they have Road Rangers.”
Alas, Mr. L’s experience is commonplace in the older set, which now goes to taverns where everybody doesn’t know your name, or sometimes theirs. An oft-heard complaint these days is “I know I came in here for something, but I can’t remember what it was. Just a second while I retrace my steps. When I get to the previous room, I always figure it out.” This is, to say the least, mildly inconvenient, if not vexing. “Where did I leave my car keys?” becomes “Where did I leave my car?” But fear not, those wily scientists who research these matters are onto something. There might be a hidden switch in your brain that could reverse memory loss. OMG, find it quick, kind sirs!
The brain lies at the biological center of our lived experience, but the scientific underpinnings of the brain---specifically, how it forms subjective consciousness---remain mysterious. Sadly, one truth is clear; as we age, so does our brain, filled with 86 billion neurons which form our experience. Any tiny dysregulation within the brain has outsized impact on its user and the direction of his/her life.
For years, scientists have tried to find ways to stave off these negative effects and make a person’s healthspan largely match their ever-increasing lifespan. In 2021, Stanford University investigated the debris-cleaning role of the myeloid cells within the brain, and three years later a study from the University of Rochester on the broader glymphatic system, which interacts with myeloid cells, found ways to restart the flow of brain-cleaning fluids.
In another installment of this ongoing research to improve the aging brain, scientists from the University of California San Francisco identified a protein which is central to aging the brain in humans. By analyzing how genes and proteins changed over time in mice, the team identified a troublesome protein named ferritin light chain 1, or FTL1. When scientists reduced the presence of this protein in the hippocampus, the mice regained some of their youthful characteristics, including improved nerve connections and better performance on memory tests. The results were published in the journal Nature Aging.
“It’s truly a reversal of impairments…much more than merely delaying or preventing symptoms,” reports Saul Villeda, co-author of the study from UCSF. “We’re seeing more opportunities to alleviate the worst consequences of old age. It’s a hopeful time to be working on the biology of aging.” To test this idea even further, the team articulately stimulated the production of FTL1 in young mice, and soon the mental abilities of the mice began to match those of older rodents. When analyzing the effects of FTL1 protein in a petri dish, Villeda and his team discerned that nerve cells engineered simple, one-armed neural wires---known as “neurites”---rather than the branching neurites typical of normal neural cells.
“To identify potential therapeutic targets to restore cognitive function in older people, we first need to gain mechanistic insight into the molecular drivers of cognitive decline in the aging brain,” the authors write. “It has become clear that cognitive dysfunction in the aged brain in the absence of neurodegenerative disease is not paralleled by cell death, but instead by a decline in neuronal function at the synaptic level.”
The authors also note that a 2015 study found that increased ferritin levels in cerebrospinal fluid negatively impacted cognitive performance and accurately predicted conversion from mild cognitive impairment to Alzheimer’s disease. The researchers hope that by targeting FTL1, future therapies may not only improve neural cognition but will also benefit people with neurogenerative disease. As this study and many before it have clearly demonstrated, there is no singular cause of mental decline. But with each new study, scientists work toward a holistic picture of neurodegenerative decline as we age, and with that new perspective comes the hope of new therapies that could make cognitive decline a thing of the past.
As Snuffy Smith once instructed, “Hitch ol’ Spark Plug to the wagon, Maw---time’s-a wastin!”
Get A Little Spine, Ernie…
They’re not just milking cows up there in the Land of 10,000 Lakes. A research team from the University of Minnesota Twin Cities recently demonstrated a groundbreaking process that combines 3D printing, stem cell biology and lab-grown tissues to provide spinal cord recovery. The news networks must have missed it with all the bickering about Charlie Kirk’s hidden vaults.
Currently there is no way to completely reverse paralysis damage, despite what Robert F. Kennedy Jr. might tell you. The problem is the death of nerve cells and the inability for nerve fibers to regrow across the injury site. This new research tackles the problem by building a bridge.
The team created a unique 3D-printed framework for lab-grown organs called an organoid scaffold, with microscopic channels. These channels are then populated with ‘spinal neural progenitor cells’ derived from adult stem cells in humans, which have the capacity to divide and differentiate into specific types of mature cells.
“We use the 3D-printed channels of the scaffold to direct the growth of the stem cells,” says Guebum Han PhD, a former U of M mechanical engineering researcher and first author of a paper on the subject published in Advanced Healthcare Materials, a peer-reviewed scientific journal. “This ensures the new nerve fibers grow in the desired way. This method creates a relay system which when placed in the spinal cord bypasses the damaged area.”
In a study funded by the NIH, the State of Minnesota Spinal Cord Injury and Traumatic Brain Injury Research Grant Program and the Spinal Cord Society, the researchers transplanted the scaffolds into rats with spinal cords that were completely severed. The cells successfully differentiated into neurons and extended their nerve fibers in both directions---rostral (toward the head) and caudal (toward the tail)---to form new connections with the host’s existing nerve circuits. The new nerve cells integrated seamlessly into the host spinal cord tissue over time, leading to significant functional recovery in the rats.
“Regenerative medicine has brought about a new era in spinal cord injury research,” says Ann Parr, professor of neurosurgery at the University of Minnesota. “Our laboratory is excited to explore the future potential of our mini spinal cords for clinical translation.
Hang on tight Lieutenant Dan, help is on the way.
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| Linlin Zhao with Yu Hsuan Chen. But you knew that, didn't you? |
If You Ain’t Got The DNA, Boys….
“….you’d better go back to beautiful Texas…Oklahoma, Kansas, Georgia, Tennessee.”---Woody Guthrie
The Grim Reaper is smiling big these days, having made enormous hauls in Gaza and Ukraine, but all is not roses and sunshine at the Death Cave. Those evil scientists are at it again, making discoveries and extending lives, and there’s no stopping them.
DNA damage makes up 2 of the 8 hallmarks of aging, and a new chemical probe has proven to protect healthy cells from DNA damage, The story of this paradigmatic development begins where so much of human health begins: the mitochondria. These organelles are often called “the powerhouses of the cell,” but they do much more than just provide cellular energy. They’re so important they even have their own DNA. Mitochondrial DNA (mtDNA) is separate from the DNA housed in a cell’s nucleus. While nuclear DNA contains the vast majority of the genetic code, mitochondria carry their own smaller genomes that are essential for cellular functions.
MtDNA exists in multiple copies per cell, but when damage occurs these copies are often degraded rather than repaired. If left unchecked, this degeneration can set off a cascade of failures linked to heart conditions, neurodegeneration and chronic inflammation. But now researchers at UC Riverside have developed a chemical probe that binds to damaged sites in mitochondrial DNA and blocks the enzymatic processes that lead to its degradation.
“There are already pathways in cells that attempt repair,” said Linlin Zhao, UCR associate professor of chemistry, who led the project. “But degradation happens more frequently than repair due to the redundancy of mtDNA molecules in mitochondria. Our strategy is to stop the loss before it becomes a problem.” The new molecule includes two key components, one that recognizes and attaches to damaged DNA and another that ensures it is delivered specifically to mitochondria, leaving DNA unaffected.
In lab tests as well as studies using living cells, the probe significantly reduced mtDNA loss after lab-induced damage mimicking exposure to toxic chemicals such as nitrosamines, which are common environmental pollutants found in processed foods, waste and cigarette smoke. In cells treated with the probe molecule, mtDNA levels remained higher, which could be critical for maintaining energy production in vulnerable tissues such as the heart and brain.
Mitochondrial DNA loss is increasingly linked to a range of diseases, from multi-organ mitochondrial depletion syndromes to chronic inflammatory conditions such as diabetes, Alzheimer’s, arthritis and inflammatory bowel disease. when mtDNA fragments escape from mitochondria into the rest of the cell, they can act as distress signals that activate immune responses. “If we can retain the DNA inside the mitochondria, we might be able to prevent those downstream signals that cause inflammation,” Zhao said. “This is a really big deal!”
Alas, there is no joy in Reaperville. The Grimster frowns, turns over his sand timer and spits in his gruel. “What a revoltin’ development THIS is,” he hisses. “Always with the damn life-saving discoveries. What we need around here is a good old-fashioned plague. Where’s that Yersinia pestis when you really need it?”
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| Longevity guru David Sinclair: "Live long and prosper." |
That’s All Well And Good, Docs, But We’re In A Hurry….
The knights might be riding back with the Holy Grail but that doesn’t help those of us who are clinging to a tree branch on the wrong side of the cliff. We’re looking for Sergeant Preston to come galloping in any minute now with a few bottles of the elixir of life in his saddlebags. We heard it on the grapevine that there are now SIX chemical cocktails out there which restore aged cells to a youthful state in under a week. Sure it sounds ridiculous, but any old port in a typhoon. The winds are blowin’ and the snows are snowin’.
Most current anti-aging approaches rely on gene therapy that alters genetic material, as we’ve seen above. Eventually, that may work for non-octogenarians, but what about those of us on the ASAP bus?
According to the Information Theory of Aging, the loss of youthful epigenetic information is the primary factor contributing to aging and age-related deterioration and dysfunction. Additionally, studies support the notion that factors such as stress or DNA damage accelerate the aging process by causing a greater loss of epigenetic information. This progressive loss can cause the cells to enter a state of dysfunction known as senescence, an irreversible state of cell cycle arrest. Senescent cells stop dividing. They also release signaling molecules that promote cell repair. As a result of aging, senescent cells accumulate in the body, contributing to the development of age-related diseases. Understanding of the aging process led scientists to seek ways to reverse age-related changes in cells.
One new study that veers from the path most traveled had researchers developing and utilizing screening methods, including the NCC (nucleocytoplasmic compartmentalization) assay. NCC distinguishes young, old and aging or senescent cells. They then identified new chemical combinations that could reverse cellular aging and rejuvenate the cells. This method was allegedly highly effective, since the treated cells supposedly regained youthful function and gene expression patterns within days. The researchers claim their results confirm the possibility that aging can be reversed in human cells without altering cellular identity or the underlying genetic code. The study identified six specific chemical cocktails that could help restore a youthful DNA methylation profile. A remarkable feature is that these compounds work at a fast rate and show results in under a week. Additionally, the cell’s original type and function are retained. Says who? We would not believe any of this if Dr. David Sinclair of the Department of Genetics at Harvard University was not involved. Sinclair is a decades-long student of longevity and the means to attain it, and one of the foremost scientists in the field.
“Until recently, the best we could do was slow aging down,” says Sinclair. “The process previously required gene therapy, limiting its widespread use.” The new cocktails use various molecules to reprogram cells, and results in mice and monkeys are positive. They are not yet available to humans, being still in the research phase. Some scientists have concerns about their safety, but hey, in the worst case how many years can they steal from an 85-year-old?
Sinclair’s team is preparing for human clinical trials, still awhile off. We’re signing up volunteers like Ron Thomas and Will Thacker, brave gentlemen always first in line to aid in advancing the horizons of mankind. Ron is still lining up a wife-care substitute and Thacker insists on some kind of guarantee that the new drugs won’t harm his punmanship, but they’re waiting at the station for pickup, ready to go where no man has gone before. The brave don’t live forever, but the overly cautious don’t live at all.
That’s all, folks….
bill.killeen094@gmail.com
