BPIFB4 Gene Linked to Longevity and Heart Health

Key takeaways:
~ Researchers have identified BPIFB4 variants in people who are long-lived.
~ BPIFB4 modulates immune response and impacts cardiovascular disease.
~ You can see if you have the BPIFB4 longevity variant in the genotype report below.

Members will see their genotype report below, plus additional solutions in the Lifehacks section. Consider joining today

BPIFB4 is identified as a longevity gene:

Healthy longevity is a goal for many of us, and genes come into play here in several ways. In general, not having deleterious genetic variants is linked to a longer overall healthspan. For example, mutations linked to hereditary cancers are associated with a shorter healthspan, and a lack of cancer-related variants is linked to an average longer lifespan.

The most common cause of death is cardiovascular disease. It’s unsurprising that a genetic variant associated with reduced cardiovascular mortality is also associated with increased life expectancy on average.

What does BPIFB4 do?

The BPIFB4 gene encodes Bactericidal/Permeability-Increasing Fold-Containing Family B member 4. It was discovered to be linked to a longer lifespan in a genome-wide association study of long-lived individuals in Italy (over age 95). The discovery spurred research into what the BPIFB4 protein does in the body and whether it can be manipulated to extend healthspan.[ref][ref]

The research on BPIFB4 is all relatively new. Researchers have found that it is a secreted protein that modulates the immune response and keeps inflammation in check. BPIFB4 is found in respiratory secretions and circulates through blood vessels. It participates in response to airborne pathogens as well as having immunomodulatory properties.[ref]

Decreasing inflammation:

Macrophages are a type of immune cell that come in two forms:

  • M1 macrophages are inflammatory, fighting off pathogens
  • M2 macrophages balance out the immune response

While we need a robust immune response against pathogens, having too much M1 activation is linked to many chronic diseases, such as heart disease. A key aspect of diseases associated with aging is that most have chronic inflammation at their roots.

BP1FB4 is involved in promoting more M2 (anti-inflammatory) macrophages.[ref] This keeps the immune response in check and thus prevents elevated inflammation in aging.

Frailty in Aging:

In aging, frailty is marked by decreased stamina, speed, activity, strength, and weight. People who are frail are more likely to have adverse events.[ref]

Gain of function mutations in BPIFB4 are linked to a significantly decreased risk of frailty in old age. Conversely, mutations that decrease the function of BPIFB4 are linked to a significant increase in the risk of frailty.

Atherosclerosis and Heart Disease:

Plaque building up in the arteries causes atherosclerosis, leading to heart disease, high blood pressure, increased heart attack and stroke risk.

A key factor in causing atherosclerosis is chronic, systemic inflammation. Gene therapy studies on BPIFB4 show that it may be able to improve cardiovascular disease. Researchers used adenovirus viral vectors to transfer the longevity variant of BPIFB4 into mice. The animals undergoing the gene therapy had reduced senescence-associated inflammation and better NAD+ levels. Intriguingly, the increased BPIFB4 variant found in humans is also associated with higher NAD+ levels.[ref]

Note that the studies on BPIFB4 gene therapy in animals are financed by a company with a patent on this as a product…

Endothelial nitric oxide synthase:

Nitric oxide is released in the endothelial cells lining blood vessels to cause the blood vessels to relax. Endothelial nitric oxide synthase (eNOS) is the enzyme responsible for creating nitric oxide from arginine. Low levels of eNOS decrease the formation of nitric oxide in the endothelium. This is one cause of higher blood pressure.

Individuals with genetically higher BPIFB4 have higher levels of eNOS, which causes the blood vessels to relax and blood pressure to decrease. Lower blood pressure and more flexibility in blood vessels are linked to better heart health (and thus longevity).[ref]

This may tie back into BPIFB4 increasing the M2 macrophages that modulate the inflammatory response. Chronic inflammation is a driving factor in heart disease and in decreasing eNOS.

Related article: NOS3 gene and endothelial nitric oxide synthase


Frailty and old age are the biggest risk factors for mortality in COVID-19.

BPIFB4 plays a role in modulating immune response, and the overactive immune response causes severe Covid symptoms and mortality. Researchers found that circulating levels of BPIFB4 correlated to worse outcomes in Covid. Additionally, the drop in BPIFB4 values correlated to disease severity.[ref]

BPIFB4 Genotype Report:

Members: Log in to see your data below.
Not a member? Join here. Membership lets you see your data right in each article and also gives you access to the member’s only information in the Lifehacks sections.


Check your genetic data for rs2070325 (23andMe v4, v5; AncestryDNA):

  • A/A: typical
  • A/G: typical longevity
  • G/G long-lived variant; gain of function; better endothelial function through increased eNOS activation[ref][ref][ref]; less likely to be frail in old age[ref]

Members: Your genotype for rs2070325 is .



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More to come?

Keep in mind that the research on BPIFB4 is pretty new – mostly within the last five years or so. This is one gene that I’m going to keep an eye out for new information.

Related Articles and Topics:

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Fighting Chronic Inflammation: Understanding the Role of TNF alpha and Your Genes
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Chronic Inflammation: Causes and Natural Solutions
Take a deep dive into the causes of chronic inflammation and learn how to target specific inflammatory pathways to reverse or prevent chronic disease.


Ciaglia, Elena, Francesco Montella, 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, 2020. Frontiers, https://www.frontiersin.org/articles/10.3389/fimmu.2020.01034.

Ciaglia, Elena, Valentina Lopardo, 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.

Dossena, Marta, et al. “New Insights for BPIFB4 in Cardiovascular Therapy.” International Journal of Molecular Sciences, vol. 21, no. 19, Sept. 2020, p. 7163. PubMed, https://doi.org/10.3390/ijms21197163.

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.

Melik, Ziva, et al. “L-Arginine as Dietary Supplement for Improving Microvascular Function.” Clinical Hemorheology and Microcirculation, vol. 65, no. 3, 2017, pp. 205–17. PubMed, https://doi.org/10.3233/CH-16159.

Mortensen, Alan, and Jens Lykkesfeldt. “Does Vitamin C Enhance Nitric Oxide Bioavailability in a Tetrahydrobiopterin-Dependent Manner? In Vitro, in Vivo and Clinical Studies.” Nitric Oxide: Biology and Chemistry, vol. 36, Jan. 2014, pp. 51–57. PubMed, https://doi.org/10.1016/j.niox.2013.12.001.

Puca, Annibale Alessandro, et al. “Single Systemic Transfer of a Human Gene Associated with Exceptional Longevity Halts the Progression of Atherosclerosis and Inflammation in ApoE Knockout Mice through a CXCR4-Mediated Mechanism.” European Heart Journal, vol. 41, no. 26, July 2020, pp. 2487–97. PubMed, https://doi.org/10.1093/eurheartj/ehz459.

Santos-Parker, Jessica R., et al. “Curcumin Supplementation Improves Vascular Endothelial Function in Healthy Middle-Aged and Older Adults by Increasing Nitric Oxide Bioavailability and Reducing Oxidative Stress.” Aging, vol. 9, no. 1, Jan. 2017, pp. 187–208. PubMed, https://doi.org/10.18632/aging.101149.

Villa, Francesco, Albino Carrizzo, Anna Ferrario, et al. “A Model of Evolutionary Selection: The Cardiovascular Protective Function of the Longevity Associated Variant of BPIFB4.” International Journal of Molecular Sciences, vol. 19, no. 10, Oct. 2018, p. 3229. www.mdpi.com, https://doi.org/10.3390/ijms19103229.

Villa, Francesco, Albino Carrizzo, Chiara C. Spinelli, et al. “Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis.” Circulation Research, vol. 117, no. 4, July 2015, pp. 333–45. DOI.org (Crossref), https://doi.org/10.1161/CIRCRESAHA.117.305875.

About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.

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