Source of Youth : Therapy with centenarian gene cause a real rejuvenation of the cardiovascular system

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Some people live much longer than average, partly thanks to their DNA.

A study, published in the European Heart Journal, shows that it could be possible to replicate this genetic gift even for those lacking it.

The way is now open to an innovative therapy model capable of preventing and fighting cardiovascular diseases through a real rejuvenation of blood vessels.

The study, conducted by the I.R.C.C.S. Neuromed, the I.R.C.C.S. Multimedica and the Department of Medicine, Surgery, and Dentistry, Salerno Medical School University of Salerno, with the support of the Cariplo Foundation and the Italian Ministry of Health, focuses on the gene that encodes the BPIFB4 protein.

In the past, the same research group had identified a variant of this gene, the so-called LAV (“longevity associated variant”), which prevails in people over 100 years of age.

Now, through a viral vector, researchers have inserted the LAV-BPIFB4 gene into the DNA of animal models particularly susceptible to atherosclerosis and, consequently, to cardiovascular diseases.

“The results – says Annibale Puca, coordinator of a research team at the University of Salerno and at I.R.C.C. MultiMedica – were extremely encouraging.

We observed an improvement in the functionality of the endothelium (the inner surface of blood vessels), a reduction of atherosclerotic plaques in the arteries and a decrease in the inflammatory state.”

In other words, the inclusion of the “centenarian gene” in animal models has caused a real rejuvenation of the cardiovascular system.

The same positive effect was also achieved in the laboratory, this time not by inserting genes, but by delivering the LAV-BPIFB4 protein to human blood vessels.

To these experimental data, researchers added further studies conducted on groups of patients.

First, they saw that at a higher level of BPIFB4 protein in the blood was associated with healthier blood vessels.

Moreover, carriers of the LAV genetic variant had higher protein levels.

Carmine Vecchione, dean of the Faculty of Medicine of the University of Salerno, says, “This study paves the way to the possibility of therapeutic solutions based on the LAV-BPIFB4 protein.

Of course, much research will still be needed, but we think it is possible, by administering the protein to patients, to slow down cardiovascular damage due to age.

In other words, even if a person does not possess those particular genetic characteristics, we could be able to offer the same level of protection.”


The aim of this study was to analyse the role of GM allotypes, i.e. the hereditary antigenic determinants expressed on immunoglobulin polypeptide chains, in the attainment of longevity.

The role played by immunoglobulin allotypes in the control of immune responses is well known as well as the role of an efficient immune response in longevity achievement. So, it is conceivable that particular GM allotypes may contribute to the generation of an efficient immune response that supports successful ageing, hence longevity.

Methods

In order to show if GM allotypes play a role in the achievement of longevity, we typed the DNA of 95 Long-living individuals (LLIs) and 96 young control individuals (YCs) from South Italy for GM3/17 and GM23+/− alleles.

Results

To demonstrate the role of GM allotypes in the attainment of longevity we compared genotype and allele frequencies of GM allotypes between LLIs and YCs. A global chi-square test (3 × 2) shows that the distribution of genotypes at the GM 3/17 locus is highly significantly different in LLIs from that observed in YCs (p < 0.0001). The 2 × 2 chi-square test shows that the carriers of the GM3 allele contribute to this highly significant difference. Accordingly, GM3 allele is significantly overrepresented in LLIs. No significant differences were instead observed regarding GM23 allele.

Conclusion

These preliminary results show that GM3 allotype is significantly overrepresented in LLIs. To best of our knowledge, this is the first study performed to assess the role of GM allotypes in longevity. So, it should be necessary to verify the data in a larger sample of individuals to confirm GM role in the attainment of longevity.

Discussion

The LLIs, i.e. those approaching 100 years of age, are a model of successful ageing. The exceptional longevity of LLIs is to some extent genetically guided, as emphasized by the family clustering of extreme longevity and the reduced mortality of the centenarian siblings compared to age-related elderly [7]. Longevity genes can be discovered by genetic association studies or GWAS conducted on LLIs [78].

These kinds of studies identify the gene variants that have been selected by the demographic pressure and, therefore, are somehow significant for human health.

The identification of these genetic variants is important since they could represent potential targets for fighting ageing-related diseases. Several research groups are working on genes involved in oxidative stress, in lipid and glucose metabolism, in immune-inflammatory responses, in DNA damage and in repair, in nutrient sensing pathways.

Many results have been obtained in association studies of candidate genes, but other results are still in conflict. In particular, to date, the majority of GWAS, that rely on large population sets for multiple testing and power issues, have only confirmed the decreased frequency of detrimental alleles of apolipoprotein E (APOE) and the increase of protective alleles of forkhead box O3A (FOXO3A) with some exceptions [710].

In the present paper we have analysed, by a classic case control study, the distribution of GM allotypes, in longevous people and controls from Southern Italy. Data show that GM3 allotype is significantly overrepresented in LLIs.

To the best of our knowledge, no study has evaluated GM allotype role in human longevity. Since the distribution of GM allotypes in the population under study is not known, a note of caution must be taken into account, because of the relatively small sample sizes of LLIs and controls. However, a study performed on the sheep several years ago reported an influence of IgG3 allotypes in ageing of sheep.

These findings, showing the role played by GM allotypes in other animal species, fit ours [11].

A study by de Vries et al. [12] is relevant to our findings. Descendants of Dutch colonists, who emigrated to Surinam and survived epidemics of typhoid and yellow fever with a total mortality of about 60%, were tested for different polymorphisms, including GM allotypes, whose frequencies were compared with those of Dutch control sample.

Several polymorphisms, including GM allotypes, were shown to influence the chance for survival, indicating selection through genetic control of immune response to pathogens. Another example of such selection is the longevity associated variant of Bactericidal/Permeability-increasing (BPI) Family B member 4 (BPIFB4), which belong to a family of proteins, BPI and lipid transfer protein (LTP), involved in the activation of toll-like receptor(TLR)-4 in the innate immune response [13].

So, it is conceivable that particular GM allotypes may contribute to the generation of a dynamic immune response that supports successful ageing, hence longevity, whereas certain other allotype combinations may produce suboptimal levels of immunity and reduced life span.

In particular, GM allotypes have been shown to be involved in the immunological control of viruses, including herpes simplex virus(HSV)-1 and human cytomegalovirus (HCMV) [1415].

Herpes viruses, such as HCMV and HSV-1, have been associated with a variety of health problems, including cognitive decline, and overall mortality in the elderly [1619].

Accordingly, recent data show that effective control of herpes viruses is impaired during healthy ageing, most probably due to loss of cellular control of early viral reactivation [2022].

Recently, an interplay between particular GM and cluster of designation(CD)16A alleles in the outcome of HSV-1 infection has been demonstrated.

The CD16A-158 V/V genotype associates with an asymptomatic course of HSV-1 infection only in homozygotes for the GM3 allele. Additional studies to determine the mechanism underlying this association showed that CD16A-158 V and GM3 alleles epistatically enhanced the antibody-dependent cell-mediated cytotoxicity (ADCC) against opsonized HSV-1-infected fibroblasts [14].

Concerning HCMV, in different populations it has been demonstrated the association of human IgG1 allotypes with immune response to the virus and some kinds of cancer thought to be associated with HCMV [2324].

More interestingly, in another Southern Italy population, GM17/17 (the alternative allele of GM3) was associated with the risk of developing HCMV symptomatic infection [15]

It is well known the role of chronic infections from herpes viruses, in particular from HCMV, in the impairment of immune responses of elderly people, hence contributing to immunosenescence [2526].

Accordingly, the severity of many infections is higher in the elderly compared to younger adults and infectious diseases are frequently associated with frailty and death. Reciprocally, an immune good function is tightly correlated to health status and longevity [42729].

On the other hand, our immune system is known to be quite efficient in fighting acute infections in young people, but not particularly efficient in responding to chronic stimuli, especially when they occur late in life.

This leads to an increased production of inflammatory mediators.

So, this chronic antigenic stress contributes to determine an inflammatory status called inflamm-ageing, responsible for age-related diseases.

Reciprocally, the control of inflamm-ageing is associated with longevity [43033].

Accordingly, an efficient control of Herpes Virus chronic infections by GM allotypes might contribute to observed association with longevity through a decrease of inflammatory status.

Several mechanisms have been proposed to explain the role played by GM allotypes in the control of virus infections. IgG allotypes might modulate avidity of the interaction of IgG with Fcγ receptor (FcγR), so influencing the efficacy of immune response.

In addition, they might modulate the strength of ADCC, thus involving cells of innate response such as natural killer (NK) cells [23].

Conclusion

This is the first report implicating GM allotypes in longevity. It needs to be replicated in an independent and larger multi-ethnic study population.

However, it has been reported that the association with longevity of other genes related to control of immune response as human leukocyte antigens (HLA) and killer immunoglobulin-like receptors (KIR), is population specific, being heavily affected by the population-specific genetic and environmental history [34].

On the other hand, it is also possible that there are other life span-associated loci on chromosome 14q32 (where the GM genes are located), distinct from GM, whose alleles are in significant linkage disequilibrium with those of the GM loci. This putative linkage disequilibrium could give rise to the associations observe.


More information: Annibale Alessandro Puca 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 (2019).DOI: 10.1093/eurheartj/ehz459

Journal information: European Heart Journal
Provided by Istituto Neurologico Mediterraneo Neuromed I.R.C.C.S.

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