What gene is most commonly up-regulated in aging (i.e. when comparing old folks to young)? The answer was surprisingly clear: serpina3, upregulated in 21% of the 331 studies. The gene has indeed been recognized as aging-related, particularly with respect to Alzheimer's disease and neurological conditions. Other upregulated genes included CD74, LYZ, HLA-DQA1, LCN2, C4B, and more. It's interesting that CD74 and HLA-DQA1 both relate to HLA Class II processes, while LYZ and LCN2 relate to anti-bacterial defense. Examining the human-only list, IGFBP3, an insulin regulator, ranks first, being found in 14% of all studies. IGFBP3 is followed by CD74, HLA-DQA1, FKBP5, CLU, and more. Serpina3 is ranked 20th in this list.
On the downregulation side, we have NREP (Neuronal Regeneration Related Protein!), found in 17% of aging studies. NREP is followed by COL3A1, COL1A1, COL1A2, and SPARC; a lot of involvement with collagen there. The human-only list is led by LRRN3, followed by ABLIM1, NELL2, BCL11A, and the above NREP.
Let's not waste time in attempting to answer the question of the moment: how do we reverse aging? Specifically, what treatments both down-regulate entities that are up-regulated in aging, and up-regulate entities that are down-regulated in aging? To answer the question, we simply load the above WIMG IDs into the "Match Studies" app, select "inverse correlations", and submit. We were pleased with the #1 ranked result, as it doesn't involve insanely expensive drugs, gene knockouts, or regimens that would be difficult to repeat in the real world: alpha-keto-glutarate (aKG) supplementation. The mouse study in question is here. Specifically, gene signatures in MSCs were examined. The aKG levels used in the study (.25-.75% in drinking water) do seem a bit difficult to replicate at home, but 1) we're talking about mice with short life spans and 2) there's no indication of a lower limit of aKG effectiveness in the study. In addition to reversing aging signatures in MSCs, aKG supplementation had a number of clear, positive effects on mouse morphology; in particular, attenuation of aging-related bone loss.
The aKG study was followed by studies that don't fall into the "try this at home" category: vegfa overexpression, and mysm ko. Abatacept, a common rheumatoid arthritis treatment, reversed the aging signature in arthritic synovium. Wonderfully, the next study in the list involves human muscle and a workout regimen: the popular HIIT training system. A little googling shows that aKG levels are indeed raised following a workout.
The list of aging-reversers did include some counter-intuitive results. In one case, macrophages from obese vs lean mice showed the reverse-aging signature. The experiment involved 24 hours gingivalis exposure; perhaps a strong short-term immune response overlaps with aging, and obese mice show a weaker immune response. Nicotine reversed the aging signature in mouse lungs.
How about treatments that are often considered as anti-aging? Resveratrol weakly trended toward downregulating transcripts that are upregulated in aging. Metformin showed no anti-aging trends whatsoever.
Examining the human-only lists, anti-retroviral treatment reversed the aging signature in infected human pbmcs. That rings a bell...we previously examined the possibility that anti-retroviral treatment could reverse Alzheimer's. Again, though, we have to concede that the anti-aging effect most likely corresponds with the killing of viruses and an accompanying decrease in inflammation; could somebody please perform some anti-retroviral studies in non-infected tissues? The mouse aKG study still strongly overlapped with with our composite lists of human-only aging studies. Fish oil treatment and vitamin D supplementation are found on the list. Fantastically, a twins study, Differences in muscle and adipose tissue gene expression and cardio-metabolic risk factors in the members of physical activity discordant twin pairs, showed that high activity (measured over a period of 30 years!) twins evinced an anti-aging signature in adipose tissue relative to their low-activity counterparts. There are a number of studies that show somewhat counterintuitive results: e.g. cancer studies where the higher-stage tissue appears younger than the lower-stage grade tissue, a study in which tissue from dementia patients is "young" relative to healthy patients, and a study in which B-cells and dendritic cells from severe Covid-19 infection patients out-younged such cells from healthy individuals.
Let's untick the "inverse correlations" box and see what conditions might actually accelerate aging. The list is led by a study involving raver2 knockout in mouse epithelial cells...not exactly something you could inadvertently perform at home. Scanning the list for at-home aging accelerators, we see cholesterol loading in mouse hearts, a variety of EAE and viral/bacterial infection studies, DHT exposure, ifn-g treatment, and a long list of other inflammatory stimuli.
Applying the same exercise with the human-only WIMG lists, we again see a fairly un-surprising litany of inflammatory stimuli inducing an aging signature. Chloroquine (remember?) treatment appears to induce aging. Hypertension patients evince a greater aging signature in pbmcs vs healthy individuals. Dexamethasone, raloxifene, and testosterone (again) enhance the aging signature. We note rosuvastatin treatment (which lowers cholesterol levels) and a lycopene-enriched diet as examples of treatments that may have effects that are counterintuitively pro-aging.
Progeria and lmna mutations are commonly associated with aging. No studies involving progeria/lmna overlapped with our aging lists, with one exception: genes upregulated in mouse heart on an lmna D300N mutation actually tended to align with genes that are canonically downregulated in aging! Hmmmm.
Biology is complex. Looking at the human up/down-regulation lists, 14 genes were actually found in both lists! These are: HLA-DRB4, THBS1, IFI44L, SPP1, RPS4Y1, IFIT1, VCAN, SNCA, S100A8, DSC2, ANXA3, IFI6, HLA-DRB1, and CD14. In the case of the HLA-related genes, we wonder if various polymorphisms are relevant to aging. The list is also loaded w/cell matrix genes and inflammation genes. Since we mixed aging-related genes regardless of tissue type, it may be possible that up-regulation of a particular gene manifests as aging-relevant in one tissue, but down-regulation manifests as aging-relevant in another.
Finally, we note that while the WIMG aging lists matched up nicely with WIMG lists involving mouse EAE, mouse Alzheimer's models, and ifn-g treatment and other inflammatory stimuli, there was no significant overlap between our aging lists and our human Alzheimer's lists, once again suggesting that Alzheimers is not merely a state of hyperaging and/or hyperinflammation.
