Reversing AGEs, and VMAT2 in Long Covid

A couple of important new studies came out this past week, prompting big updates on Genetic Lifehacks.

VMAT2 in Long Covid:
A study using brain scans of long Covid patients (compared with matched, healthy controls) found that VMAT2 levels were significantly lower in certain regions of the brain.

What is VMAT2? It’s the transporter that moves dopamine and other monoamine neurotransmitters into vesicles inside neurons. These vesicles release the neurotransmitter when needed, which is an essential way that neurotransmitter levels are controlled.

VMAT2 is particularly important for packaging dopamine. Excess dopamine in the neuron’s cytosol can oxidize and become neurotoxic, so VMAT2 both regulates how much is released and protects the neuron from the toxicity of free-floating dopamine.

In long Covid, the lower VMAT2 levels in the dopaminergic neurons correlate with the neurological symptoms of apathy, memory decline, and even slowed motor function (speed of physical movements).

My VMAT2 article is now updated and vastly expanded. In it, I explain the genetic variants, the connections to Parkinson’s and neurodegenerative diseases, and the research on PTSD and anxiety. Environmental factors that can decrease VMAT2 include certain pesticides, flame retardants, and heavy metals — as well as chronic cocaine or methamphetamine use.

AGEs and falling apart in aging:
Advanced glycation end products (AGEs) are compounds formed in the body during metabolism (especially glycolysis) and formed in foods by the Maillard reaction - the browning of meat or baked goods. AGEs then irreversibly modify proteins in the body. For example, AGEs are involved in the cross-linking of collagen that causes stiffening of tendons or wrinkling of the skin.

AGEs accumulate with aging, and they cause inflammation through activation of the receptor for advanced glycation end products. All in all, AGEs end up being one of the causes of much of what goes wrong in aging.

What prompted this big article update? There’s a new study out showing an engineered enzyme can now reverse what was thought to be irreversible. The enzyme removes a specific type of advanced glycation end product that builds up and triggers chronic inflammation — essentially reversing decades of aging. Here’s an easy-to-read article on the study.

There are also a bunch of natural supplements that can help reduce the production of AGEs, and genetic variants that can increase or decrease AGEs. I cover all of that in the Advanced Glycation End Products article and genotype report.

Coming next week:
I’m working on a new article about the genetic causes of hypophosphatasia and low ALP levels.

Gratefully yours,

~ Debbie

What I’ve been reading:

Urolithin A for heart failure
A new study (in animals) shows that urolithin A can help to restore mitochondrial function in heart failure. They were able to reverse much of the damage in heart failure with urolithin A in a mouse model of heart failure. I hope they do clinical trials on urolithin A for heart failure soon to determine dosing in humans!

Diverticular disease genome-wide association meta-analysis identifies 257 novel loci, implicates structure and motility (Preprint)
A massive new genetics study involving 157,000 cases of diverticulitis and 1.2 million controls shows that genetic variants in colonic smooth muscle, fibroblasts, and intestinal cells are at the root of susceptibility.

Vagal cholinergic denervation of the gastric mucosa in Long-COVID-19: in vivo evidence of structural autonomic dysfunction
Researchers looked at stomach biopsies from long Covid patients and counted the nerve fibers in them. The patients had persistent gastrointestinal symptoms and dysautonomia after Covid infection. The results showed that the patients had a significant loss of cholinergic nerve fibers in the stomach (about half of the nerve density compared to the healthy controls).

Plasma GDF15 affects long-term dementia risk and alters neuroimmune signaling
From the study: “Growth/differentiation factor–15 (GDF15) is a secreted cytokine strongly associated with dementia risk...” Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer’s disease (AD), dementia. Two-sample Mendelian randomization supported plasma GDF15’s mechanistic role in AD and related dementias, while cohort studies linked it to cerebral small vessel disease, neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuroimmune activation.