Information Wellness Blog

Researchers reported in mSystems that giving old mice fecal transplants from younger mice can reverse some signs of aging. The transplants helped stimulate more new neurons to grow in older brains while increasing myelin sheath thickness around nerve cells.

Sinclair and his team utilized ICE to make temporary, fast-healing cuts in mice’s DNA that mimicked lifestyle and environmental influences on their epigenetic pattern. After one month of treatment, these mice looked and behaved much younger.

Epigenetics

Scientists have long speculated that mutations to DNA are one of the primary contributors to aging, but recent research indicates non-genetic causes may also play a part. Epigenetics — using chemicals that turn on or off genes without altering DNA sequence — also plays a significant role. Researchers are still learning more about their effect, with hopes that harnessing their power for manipulating gene expression could slow or reverse aging and associated diseases.

One famous example is the development of a caterpillar into a butterfly in its chrysalis. While their genes remain the same, their expression in their new cells differs due to their new environment; epigenetic factors play an integral part in controlling how genes are expressed.

Epigenetics affects all cells in the body, from stem cells that can develop into any cell type to those that divide rapidly and repair themselves regularly. They also may play an integral part in cancer formation as well as other diseases and abnormalities.

Researchers conducted their study by treating adult mice with a mixture of four Yamanaka factors that reset epigenetic markings on stem cells within their bodies back to their original patterns, turning embryonic or pluripotent stem cells into something they could develop into any cell in their bodies.

Once treated for seven to ten months, scientists observed that their tissues, kidneys and skin looked significantly younger than untreated mice; treatment also significantly slowed normal tissue aging processes.

Scientists believe this result demonstrates it is possible to delay and reverse aging through manipulation of epigenetic processes. They plan on further studies in order to better understand how long-term treatments with Yamanaka factors could help delay aging and its health consequences, as well as identify which molecules contribute to youthful cells and how these could be modified in future studies.

Telomerase

Telomeres are DNA sequences at the ends of chromosomes that gradually shorten each time cells divide, leading to cellular senescence and eventually disease in cells. Telomerase can counteract this cellular senescence and maintain telomere length; researchers have discovered that adding it into cells significantly increased lifespan and health outcomes; natural substances like resveratrol and quercetin also help increase this process.

Houston Methodists Research Institute in Texas recently demonstrated that human telomeres can be extended through gene therapy. A team of scientists used embryonic stem cells with long telomeres, infusing the gene that encodes telomerase with gene therapy to create mice with longer telomeres than usual that showed signs of rejuvenation, including reduced inflammation and improved metabolism, as well as longer lifespan than mice with normal telomeres.

Further, they demonstrated that having long telomeres did not correlate with cancer risk. Tumor cells do not use telomerase for maintaining telomeres and instead use another pathway instead; if their RNA template becomes damaged or blocked however, cancer cells will eventually die off, underscoring its importance for human longevity.

Houston Methodists team then used this same approach to extend telomeres of progeria cells from patients suffering from Hutchinson-Gilford progeria syndrome – an accelerated form of aging leading to premature vascular aging. Their study showed that treatment with telomerase improved endothelial cells that line our blood vessels as well as reduced senescence and SASP factors that impair them, thus restoring proliferation capabilities of these ECs and decreasing effects associated with vascular aging.

Hyper-long telomere mice displayed a younger metabolic phenotype that was linked with protecting glucose homeostasis and decreasing fat accumulation in liver and brown adipose tissues. Furthermore, they had lower cholesterol and liver damage marker ALT blood levels than typical mice and may provide protection from metabolic disorders due to increased telomere length.

Yamanaka factors

Shinya Yamanaka and his team used techniques similar to embryonic stem cell production to unlock non-embryonic skin cells into embryonic-like states using specific genes, known as induced pluripotent stem cells (iPSCs), creating cells capable of turning into any cell type within the body allowing researchers to study cell development, regenerative medicine and other fields that would otherwise be impossible.

Yamanaka and his team’s findings marked the first evidence that living organisms could reverse aging through epigenetic manipulation. Their studies then confirmed this by applying similar reprogramming factors to pancreatic cells, skeletal muscle cells and blood cells – with results showing aging-related processes being speeded up or stopped entirely by using these reprogramming factors to reset epigenetic marks and reset epigenetic marks with them.

But, these studies were performed on isolated cells in a petri dish; therefore, recreating these results in living animals would be impractical, since it’s impossible for cells within an organism to forget who they are; for instance a heart cell simply can’t forget it’s supposed to pump blood, while switching back into its developmental state would render it incapable of pumping properly.

To circumvent this obstacle, scientists turned to partial reprogramming. By adding more factors to their OSKM mixture, they were able to turn adult fibroblasts into cells that acted similar to embryonic stem cells – creating an easier method for turning cells into iPSCs than traditional processes.

Researchers conducted subsequent experiments analyzing the effect of altering transcription factor levels in older fibroblasts. They discovered that raising levels of two transcription factors, EZH2 and E2F3 while simultaneously decreasing those for STAT3, ZFX and ZFX led to more rapid cell reprogramming; moreover, these manipulations did not damage DNA nor result in mutations associated with cancer.

Yamanaka and his team then studied the effects of reprogramming on living animals. They found that injecting progeric mice with iPSCs from young mice partially reversed several symptoms associated with aging, such as increased grip strength, decreased anxiety behavior and enhanced tissue regeneration in pancreas and skeletal muscles. Reprogramming also significantly accelerated telomere shortening rate as well as decreasing mitochondrial dysfunction.

NAD+

Nicotinamide Adenine Dinucleotide (NAD+), an essential cofactor in many metabolic pathways, decreases with age. Depletion of NAD+ has been associated with mitochondrial dysfunction, DNA damage repair failures, genomic instability, inflammation, cell senescence and neurodegeneration – hallmarks of the aging process.

Researchers from MIT have developed an artificial enzymatic system to produce NAD+ in their laboratories and found it significantly extended the lives of mice. Their new approach utilizes P7C3-A20 as an inhibitor to boost key enzymes involved in NAD+ synthesis; P7C3-A20 also restored NAD+ levels in two Alzheimer’s mouse models and reduced symptoms associated with their diseases – their results published in Cell Metabolism.

Researchers discovered that even minute amounts of nicotine, a natural by-product of the NAD+ pathway, could significantly boost biogenesis of NAD+ and improve glucose metabolism in older mice. NAD+ is essential to sirtuin proteins which regulate DNA repair and energy generation within cells; increasing biogenesis through nicotine could provide a novel approach to slowing aging.

A 5xFAD model used 18F-FDG PET imaging to monitor glucose metabolism in mouse brain and heart tissues of treated mice. Researchers discovered that increasing NAD+ levels reversed glucose hypermetabolism, improving cognitive performance while simultaneously decreasing signs of inflammation and stress in brain tissue – results which support previous findings suggesting nicotine can enhance both metabolic health and cellular wellbeing in older animals.

NAD+ is broken down by an enzyme known as PARP1 to release NAM and ADP-ribose that are then processed through the Krebs cycle into ATP for production of energy in cells. If NAD+ levels drop too low in cells, oxidative stress occurs which leads to premature aging and age-related illnesses.

Researchers conducted a study revealing that raising NAD+ levels using the P7C3-A20 compound increased NAD+ levels in older mice’s brains and prevented measures of disease while making them look biologically much younger. Furthermore, raising these NAD+ levels repaired blood-brain barrier integrity while stopping progression of DNA damage; suggesting this approach could change our current view that Alzheimer’s is irreversible.