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Restless leg syndrome affects somewhere between 4 and 14% of adults, and the go-to internet advice is to take iron.
That may not be the right move for everyone. People with RLS often have low iron in the brain even when blood ferritin looks normal. A 2025 study found ferroptosis, an iron-driven type of cell death, ramped up in dopamine neurons in RLS, triggered by changes in the body clock. Adding more iron when ferritin is already fine could make that worse.
A few other clues from the research. People with MCAS were about 3 times more likely to have RLS. SSRIs, SNRIs and tricyclics raised the odds of leg movements in sleep. Higher folate went along with more risk, and higher magnesium with less.
geneticlifehacks.com/restles…
Interesting and large study - interesting because HDL levels have genetic connections. Going to update my articles on HDL and APOB today.
New study using UK Biobank data finds that HDL ("good") cholesterol attenuates the risk of ApoB for coronary heart disease.
In effect, if HDL is high, then ApoB doesn't matter much if at all.
HDL is a marker of metabolic health. academic.oup.com/eurjpc/adva…
Reposting this to highlight all of the good comments on LDN from people who have tried it.
This one is likely to be disappointing for a lot of people who feel LDN helps them.
A placebo-controlled trial in post-COVID ME/CFS found no real difference in fatigue or pain.
one thought, though. LDN is thought to work partly by calming TLR4 signaling in microglia, and people vary a lot in opioid receptor and TLR4 genetics. Average results can hide a subgroup (with genetic variants) that responds.
Has LDN helped you, or did it do nothing?
A new PNAS paper used insurance claims from 245 million Americans to answer an interesting question:
Which long COVID symptoms are actually caused by COVID?
Most earlier studies compared people with a COVID diagnosis to people who never had one.
The catch is that people who got Covid tests were often already at the doctor for something else.
So this team compared people who tested positive to people who tested negative and looked at health outcomes of each group.
Out of 614 health outcomes, the number that were statistically linked to COVID at 1 to 4 months dropped from 262 to 43.
From 4 months to a year it was just 5, including muscle problems, hair loss, and blood clots in the lungs. After a year, nothing stood out.
The older studies on Covid even linked Covid infections to lightning strikes and gun injuries... which tells you something was off.
The authors say clearly that this doesn't mean symptoms after a year aren't real -- just that claims data can't show COVID caused them.
Note that home tests weren't counted, and up to 20% of the negative group later tested positive.
So study design matters a lot, good data matters a lot, and people still sick a year later deserve real answers on what is going on for them.
Thoughts?
Full paper is open access - read it for yourself :-) pnas.org/doi/10.1073/pnas.26…
For years, researchers claimed 400 million+ people contract Long COVID, it has 200+ symptoms, and 90% never recover
Our @PNAS paper shows these findings are incorrect b/c of bad study design. Symptoms are real, but most due to other illness, not COVID pnas.org/doi/10.1073/pnas.26…
The idea that BCG might lower Alzheimer's risk came from bladder cancer patients, where retrospective studies found 12 to 78% lower incidence after BCG.
This mouse study gets at the "why".
BCG seems to retrain the myeloid immune cells and calm down neuroinflammation, with less phospho-tau produced.
Big mouse study caveat, but it's another piece of the immune and infection angle in dementia. I want to see human trials and the risk/benefits for BCG.
A new study proposes the Bacillus Calmette-Guérin vaccine as a preventative measure against dementia.
The vaccine reduces Alzheimer’s-associated phospho-tau proteins, reprograms myeloid immune cells and limits neuroinflammation. scim.ag/4hZ0wN1
Pre-print on the idea that high homocysteine could play a causal role in long Covid and ME/CFS. It makes sense. But I'm also really surprised that something as easy to test as homocysteine levels hasn't already been tested for long Covid. The idea is that homocysteine gets converted to a thiolactone that damages proteins and the lining of blood vessels.
May be of interest to #pwLC #pwME Kell, D. B. & Pretorius, E. (2026) Evidence for the Causal Involvement of Homocysteine in Long COVID and ME/CFS. Preprints. 2026, 2026102574. doi.org/10.20944/preprints20…
It's interesting that the signal was in genes tied to platelet count. People in the top 20% for the platelet polygenic score had 1% dementia on aspirin vs 3.3% on placebo. But major bleeding went from 2.1% to 4.4% in that same group, so it's definitely a talk to your doctor situation for your individual bleeding risk factors.
However, it does point to microvascular clotting as a part of dementia risk that is worth more attention.
A post-hoc genetic analysis from Monash University, utilizing data from more than 13,500 participants in the ASPREE (Aspirin in Reducing Events in the Elderly) trial, indicates that daily low-dose aspirin may significantly decrease dementia risk, though only within a highly specific genetic subgroup.
While previous comprehensive assessments of the trial cohort revealed no general cognitive protection from aspirin, this localized study identified a 70% relative reduction in dementia incidence among older adults who ranked in the top 20% for a polygenic risk score tied to high platelet counts. In this distinct subgroup, dementia developed in only 1.0% of the aspirin group compared to 3.3% of the placebo group, representing an absolute risk reduction of 2.3 percentage points.
However, this apparent neuroprotective benefit is accompanied by a severe safety trade-off. Among the exact same genetic subpopulation, the incidence of major internal bleeding more than doubled, climbing from 2.1% in the placebo group to 4.4% among those taking aspirin. This parallel increase matches the absolute difference seen in dementia reduction, meaning the statistical probability of experiencing a major hemorrhage is equivalent to the probability of preventing cognitive decline.
The biological significance of this discovery lies in its departure from typical Alzheimer's disease pathways, such as the APOE gene. Instead, the data points heavily toward platelet-related genetics and microvascular mechanisms, opening a new door for personalized medicine and targeted preventative therapy. Despite these intriguing insights, the findings do not confirm that the cognitive rewards outweigh the bleeding hazards. Because the data stems from an exploratory subgroup analysis, experts emphasize that individuals should not self-prescribe low-dose aspirin for dementia prevention without consulting a physician. Further clinical trials explicitly designed around this specific platelet genetic profile are required to validate the results.
[Fransquet, P. D., et al. (2026). Platelet count polygenic scores may modify the effect of aspirin in primary prevention of dementia. Alzheimer's & Dementia, 22(9), e71817. DOI: /10.1002/alz.71817]
good point. It could be a combination of their inherited TLR4 variants -- as well as whether TLR4 is involved in ME/CFS for that patient.
Not everyone with PCOS has ovarian cysts, and not everyone with ovarian cysts has PCOS.
PCOS affects about 5 to 18% of premenopausal women and is estimated to be around 70% heritable. There isn't one PCOS gene, though. The research points to four overlapping pathways, which are hormone dysregulation, insulin resistance, circadian disruption and inflammation.
The insulin piece runs both ways. Insulin pushes the ovaries to make more testosterone, and giving women testosterone increases insulin resistance.
The circadian piece is the one I find most interesting. In animal studies, disrupting the body clock with light caused the same hormone changes seen in PCOS. So late nights under bright lights may matter more than most people think.
Knowing which pathway is driving yours helps you decide what to work on first. 👇
geneticlifehacks.com/genetic…
It's good to see more clinical trials using repurposed drugs for Alzheimer's.
It's interesting, though that they chose metformin and atomoxetine.
Here's a prior phase II trial on Atomoxetine that showed no cognitive benefits in 12 months. Small trial, though, so maybe a larger one will show statistically significant changes.
pmc.ncbi.nlm.nih.gov/article…
Diabetes and ADHD drugs to be tested on Alzheimer's patients in new study | Fergus Walsh, BBC
A clinical trial has been launched in the UK which scientists hope could cut years from the search for new treatments for Alzheimer's disease.
It will test multiple drugs simultaneously, starting with two repurposed medicines already used to treat type 2 diabetes and attention deficit hyperactivity disorder (ADHD).
The study will examine whether the drugs can lessen symptoms such as memory and thinking problems, and help people maintain their quality of life.
Angela Bucksey, 67, from Cambridgeshire, was diagnosed with Alzheimer's in January and is the first person to begin treatment on the trial, called AD-SMART.
"We have Alzheimer's in the family," she told the BBC.
"My mother had it and my aunts, so it was a disappointment rather than a shock when I was diagnosed because I knew it would restrict my life.
"But I was determined that it wasn't going to define me."
Angela said she felt empowered joining the trial because "at least you are doing something".
"Instead of just sitting there, you're standing up and saying, I will fight back."
Alzheimer's is the most common type of dementia, affecting around 600,000 people in the UK.
'Cutting-edge treatments'
Prime Minister Andy Burnham, whose father died from Alzheimer's last month, said he knew how it felt to lose a loved one to dementia, and had seen first-hand the devastating impact of the disease on families.
"That's why I'm proud to see this trial being launched in the UK, so that cutting-edge treatments can reach patients here as soon as possible," he said.
The AD-SMART study is what's known as a multi-arm, multi-stage platform trial where several treatments are tested simultaneously, with the results compared with one group of participants taking a placebo or dummy.
This means those involved have a higher likelihood of getting an active treatment than in a traditional trial.
If any drug isn't showing benefit it can be dropped quickly and a new treatment added in its place - the approach has been used successfully in cancer and motor neurone disease.
The two initial drugs being tested are metformin, used to treat type 2 diabetes, and atomoxetine, for ADHD, which were selected by an international panel of experts.
Both drugs may help reduce brain inflammation, which is a driver of neurodegeneration, said chief investigator Prof Paresh Malhotra, group leader at the UK Dementia Research Institute Centre for Care Research & Technology at Imperial College London.
"For too long, Alzheimer's research has moved at the pace of one drug, one trial, one answer - sometimes taking a decade or more before we know if we've found something that works," he told the BBC.
"We are applying advances from cancer and other conditions to accelerate testing of treatments for people with Alzheimer's disease."
'Back from despair'
For the drugs to be successful, the study has to show that they have beneficial effects on thinking and the ability to carry out everyday activities.
"That's what patients and their carers care about," said Prof Malhotra.
Some 1,200 participants with mild to moderate Alzheimer's will be recruited at more than 30 sites across the UK. Sites in Cambridgeshire, Surrey, London, Southampton and Edinburgh are already open.
Scientists expect to finish evaluating the first drugs in 2030 and, in that time, additional treatments are likely to be added.
All the participants will have regular health checks including cognitive tests, which will help researchers assess how effective the treatments are.
Angela Bucksey's husband Steve, who is her study partner, told the BBC: "Joining the trial has brought us back from the despair of a diagnosis which everybody recognises is non-recoverable.
"People who know we are on a drug trial understand that we're doing something about it and, rather than be sorry for us, they can be encouraging."
Dr Sheona Scales, director of research at Alzheimer's Research UK said "time is precious" for people living with Alzheimer's disease and more treatment options are urgently needed.
Read more:
bbc.co.uk/news/articles/cqly…
Interesting saffron study in perimenopause. The mood and anxiety improvements fit with older research, where saffron seems to act on serotonin and also has anti-inflammatory effects. The caveats in this thread are worth reading though. It's industry funded, not peer reviewed yet, and the effect is double the earlier trial. Still, there aren't a lot of drawbacks to trying saffron.
Here's more research studies on saffron: geneticlifehacks.com/saffron…
A saffron extract cut perimenopausal symptom scores by 68% in 12 weeks versus 17% on placebo, roughly twice the benefit a similar saffron trial reported five years ago.
Saffron’s most consistent evidence is for mood, and a 2019 meta-analysis of 23 trials found large effects on depressive and anxiety symptoms compared with placebo, although it also found signs of publication bias and little regional diversity. In menopause, a 6-week trial in postmenopausal women with depression and hot flashes reported improvements in both. The closest comparison is a 2021 Australian trial in 86 perimenopausal women, where a different extract at 28 mg a day lowered total symptom scores by 32% versus 14% on placebo, with clear gains in anxiety and depression but nothing beyond placebo for hot flushes or physical symptoms.
Those studies left the size of saffron’s effect across perimenopause uncertain. In the new preprint, 104 women in perimenopause at three sites in Pakistan were randomized, double-blind, to 30 mg a day of a standardized extract or placebo for 12 weeks, with symptoms rated on the 21-item Greene Climacteric Scale.
1. Total scores fell from 35.2 to 11.2 on saffron and from 35.6 to 29.4 on placebo, and most of the saffron effect had appeared by week 6, when scores were down 44% versus 10%.
2. Psychological symptoms fell 67% versus 16%, and physical symptoms such as headaches, aches and dizziness fell 75% versus 18%, while the combined hot flush and night sweat score narrowly missed significance even though night sweats improved.
3. Mood scores, rated sleep quality, several quality-of-life measures and triglycerides also improved, and mild side effects were similar in both groups (10 versus 8 events).
Taken together, the direction matches earlier saffron research, especially for mood, but the size does not. Placebo groups improved by similar amounts in both perimenopause trials (14% and 17%), while the saffron effect more than doubled, from a 32% drop to a 68% drop. For women whose perimenopause is dominated by anxiety, low mood and low energy, saffron is a reasonable option to discuss, but the 68% figure should be treated as a ceiling until an independent group repeats it.
This is a preprint that has not been peer reviewed, the extract’s maker funded the trial, and four authors work for the company. Only 63 of 104 women fully followed the protocol, and several smaller results faded when the analysis was limited to them. The paper reports that hot flushes improved no more than on placebo, yet its own table shows scores falling from 2.0 to 0.6 on saffron versus 2.0 to 1.5 on placebo, an inconsistency the authors need to resolve. Women using hormone therapy, antidepressants or sleep medication were excluded.
References
Sultana R et al., medRxiv (preprint), 2026
Lopresti AL and Smith SJ, Journal of Menopausal Medicine, 2021
Marx W et al., Nutrition Reviews, 2019
Kashani L et al., Archives of Gynecology and Obstetrics, 2018
This one is likely to be disappointing for a lot of people who feel LDN helps them.
A placebo-controlled trial in post-COVID ME/CFS found no real difference in fatigue or pain.
one thought, though. LDN is thought to work partly by calming TLR4 signaling in microglia, and people vary a lot in opioid receptor and TLR4 genetics. Average results can hide a subgroup (with genetic variants) that responds.
Has LDN helped you, or did it do nothing?
This is one of my favorite aging studies - from a couple of years ago, I think.
IL-11 is an inflammatory signal that climbs with age, and blocking it in older mice extended median lifespan by about 25% in both males and females.
The treated mice also had less frailty, better metabolism, and fewer cancers. IL-11 seems to drive aging partly by keeping mTOR switched on, the same growth pathway rapamycin targets.
Mouse study, and the antibody isn't available for people... But there are some ways to impact IL-11 that I wrote about here: longevitylifehacks.substack.…
These two mice are the exact same age, the human equivalent of 85.
The mouse on the right was given an antibody blocking a single inflammatory protein (IL-11) starting in late middle age.
Starting treatment at human-equivalent age 55:
- Extended median lifespan by 25% in both males and females
- Prevented grey hair, frailty, and muscle wasting
- Cut late-life cancer deaths in half
Three anti IL-11 antibodies (that might extend human lifespan) are already in human clinical trials right now.
Interesting study. Creatine plus lifting twice a week, and perimenopausal women had more regular sleep and fewer days of feeling overheated or hot flashes.
There's actually a neat hormone link here. The brain uses creatine to recycle ATP through an enzyme made by the CKB gene, and CKB was originally discovered as a protein that estrogen switches on. So when estrogen drops, brain energy can be affected.
Creatine may help women in perimenopause maintain more consistent sleep when combined with strength training.
Women taking creatine for 6 weeks had sleep regularity scores 7.4 percentage points higher than the placebo group, reported fewer days of temperature sensitivity, and had greater brain oxygenation during a cognitive task.
The protocol was 20 grams of creatine monohydrate daily for 5 days, followed by about 4.5 grams daily, with resistance training twice a week.
These are encouraging early findings, particularly for sleep regularity in a population known to suffer from poor sleep quality!
I love seeing more creatine research in women.
pubmed.ncbi.nlm.nih.gov/4292…
A new study in Cell found that taurine levels don’t drop with age (the way they measured them). Yet supplementing with taurine was still beneficial in aging mice. The mechanism is interesting. Taurine helped to prevent excess NLRP3 activation - preventing inflammaging, of this sort.
Here’s my latest Longevity Lifehacks article on it. longevitylifehacks.substack.…
T cells can get worn out. Researchers call it T cell exhaustion, and most of the early work came from HIV and hepatitis C patients in the 90s.
When a T cell keeps seeing the same antigen for too long, it turns up brakes like PD-1, TIM3, CTLA-4 and LAG-3 and stops responding well. In mice, 1 to 2 weeks of antigen made healthy memory T cells, while 2 to 4 weeks pushed them toward exhaustion. It works more like a dimmer switch than an off switch.
A portion of long Covid patients show this pattern, and a 2024 study found it was common in ME/CFS. In one study, when treatment improved CD8+ T cell function, symptom severity dropped by more than half. By 24 months, many long Covid patients had T cells that looked more normal again, along with better quality of life.
Exhausted T cells also tend to have struggling mitochondria. Genetic variants shift how easily you hit that threshold. 👇
geneticlifehacks.com/t-cell-…
Histamine dark circles is one of the real ones on this list.
Allergic shiners come from congestion and dilated blood vessels under the eyes, and they show up a lot in people with allergies and mast cell issues. However, this doesn't mean it's always histamine... Thin under-eye skin (often in aging) and plain old genetics can do it too.
Good video for POTS Awareness Day.
Something I wish more people knew is how often POTS coexists with other things, like hEDS, mast cell issues, ME/CFS, and long Covid.
A big share of long Covid patients end up with some form of dysautonomia.
More on the background science and genes that increase susceptibility here: geneticlifehacks.com/genetic…
