BPIFB4: Longevity benefits, new oral formula
It's a mouse study, but this could be big!
A new study on BPIFB4 caught my eye recently. BPIFB4 is a gene and protein that made headlines a few years ago as being associated with increased odds of living past 100.
Let me give you a little background on BPIFB4 first, and then we’ll dive into the details of the new study.
Background: What does BPIFB4 do?
About a decade ago, the BPIFB4 gene was discovered in a genome-wide association study to be associated with longevity. Researchers in Italy were looking at people aged 95+ to see what was genetically different, and they found a variant in the BPIFB gene that they called the longevity-associated variant (LAV-BPIFB4 — researchers love acronyms). The discovery spurred research into what the BPIFB4 protein actually does in our bodies and whether it might hold the key to extending not just lifespan, but healthspan.12
BPIFB4 is a secreted protein that modulates the immune response and keeps inflammation in check. Found both in respiratory secretions and circulating through our bloodstream, BPIFB4 helps defend against airborne pathogens while simultaneously fine-tuning our immune system’s responses.
Long-lived people were more likely to have more BPIFB4 due to the longevity-associated variant. (Check your BPIFB4 genes here.)
Frailty in Aging:
As we age, frailty creeps in - decreased stamina, speed, activity, strength, and weight. People who are frail are more likely to have adverse events.
Here’s where BPIFB4 is important: people carrying gain-of-function mutations in this gene show significantly lower rates of frailty in old age. The flip side is equally telling - people with mutations that decrease BPIFB4 function have markedly higher frailty risks.
Atherosclerosis and Heart Disease:
BPIFB4 also influences blood vessel health. Plaque building up in the arteries causes atherosclerosis, leading to heart disease, high blood pressure, increased heart attacks, and strokes.
A key factor in causing atherosclerosis is chronic, systemic inflammation. Gene therapy studies on BPIFB4 in mice show that it may be able to improve cardiovascular disease. Researchers used adenovirus viral vectors to transfer the longevity variant of BPIFB4. The animals undergoing the gene therapy showed reduced inflammation associated with cellular senescence and improved NAD+ levels, which typically decline with age. Intriguingly, the increased BPIFB4 variant found in humans is also associated with higher NAD+ levels.3
Other recent studies show that the LAV-BPIFB4 version improves vascular health by increasing endothelial nitric oxide synthase as well as acting on two protein kinases.4
So we have several things going on with higher BPIFB4 levels: less frailty, less heart disease, and more NAD+ to boost mitochondrial health.
New study:
Researchers had previously created a genetically edited mouse version of the LAV-BPIFB4 variant and found that it reduced the risk of cardiovascular disease and inflammation.
The new study on BPIFB4 used an oral version of the longevity-associated variant of BPIFB4 as a recombinant protein. While small, the study showed that oral administration of BPIFB4 prevented atherosclerosis and preserved the integrity of blood vessels. Moreover, the mechanism here was that it reduced IL-1α, IL-1β, TNF-α, and IL-6 (pro-inflammatory cytokines) even in metabolically unhealthy mice fed a high-fat diet. 5
Why is this cool? No one wants to be gene-edited like a mouse, so the fact that an oral version of the protein survives the stomach and could be absorbed is potentially a huge breakthrough. As usual, more studies are needed!
While we wait…
While we wait to see if BPIFB4 orally has positive effects in humans, here are a few ways to target the same pathways for healthy aging.
NMN or NR: One benefit of BPIFB4 for longevity is the increase in NAD+ levels, which decline in aging. Nicotinamide riboside* or NMN can also increase NAD+ levels.[ref][ref][ref]
Curcumin or quercetin can help to tamp down inflammation.[ref][ref] For anyone with genetic testing, check your COMT gene to make sure that you don’t have interactions with this supplement.
Ciaglia, Elena, et al. “Circulating BPIFB4 Levels Associate With and Influence the Abundance of Reparative Monocytes and Macrophages in Long Living Individuals.” Frontiers in Immunology, vol. 11, May 2020, p. 1034. PubMed Central, https://doi.org/10.3389/fimmu.2020.01034.
Malavolta, Marco, et al. “LAV-BPIFB4 Associates with Reduced Frailty in Humans and Its Transfer Prevents Frailty Progression in Old Mice.” Aging (Albany NY), vol. 11, no. 16, Aug. 2019, pp. 6555–68. PubMed Central, https://doi.org/10.18632/aging.102209.
Ciaglia, Elena, et al. “Transfer of the Longevity-Associated Variant of BPIFB4 Gene Rejuvenates Immune System and Vasculature by a Reduction of CD38+ Macrophages and NAD+ Decline.” Cell Death & Disease, vol. 13, no. 1, Jan. 2022, p. 86. PubMed, https://doi.org/10.1038/s41419-022-04535-z.
Calligaris, Matteo, et al. “Protective Role of the Longevity-Associated BPIFB4 Gene on Cardiac Microvascular Cells and Cardiac Aging.” Vascular Pharmacology, vol. 158, Mar. 2025, p. 107470. ScienceDirect, https://doi.org/10.1016/j.vph.2025.107470.
Ciaglia, Elena, et al. “In Vivo Evidence Supports the Effectiveness of the Longevity-Associated Protein LAV-BPIFB4 in Reducing Adipose Tissue-Derived Mediators of Systemic Inflammation to Prevent Vascular Insult and Atheromatous Change.” Adipocyte, vol. 14, no. 1, Dec. 2025, p. 2580152. DOI.org (Crossref), https://doi.org/10.1080/21623945.2025.2580152.
* Amazon affiliate link. These brands are just suggestions — read reviews and choose the brand you think is best.