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(Circulation. 2004;110:3108-3114.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Balanced Regulation of mRNA Production for Fas and Fas Ligand in Lymphocytes From Centenarians

How the Immune System Starts Its Second Century

Marcello Pinti, PhD; Leonarda Troiano, PhD; Milena Nasi, PhD; Cristian Bellodi, BSc; Roberta Ferraresi, BSc; Chiara Mussi, MD, PhD; Gianfranco Salvioli, MD; Andrea Cossarizza, MD, PhD

From the Department of Biomedical Sciences, Chair of Immunology (M.P., L.T., M.N., C.B., R.F., A.C.), and Department of Internal Medicine, Chair of Geriatrics (C.M., G.S.), University of Modena and Reggio Emilia, Modena, Italy; and Laboratory of Genetic Instability II, MRC Toxicology Unit, University of Leicester, Leicester, UK (C.B.).

Correspondence to Andrea Cossarizza, MD, PhD, Department of Biomedical Sciences, Via Campi 287, 41100 Modena, Italy. E-mail cossariz{at}unimo.it

Received December 8, 2003; de novo received April 10, 2004; revision received June 9, 2004; accepted June 10, 2004.

Background— The functionality of the immune system during aging is crucial for protection against the most common age-related diseases. Apoptosis plays a central role in the senescence of the immune system, as evidenced by the increased plasma membrane expression of a key molecule like Fas protein. We analyzed the mRNA levels of different forms of Fas (total [tFas] and membrane [mFas]) and of its ligand (FasL) in peripheral blood lymphocytes from centenarians, the best example of successful aging, who were compared with young and middle-aged donors.

Methods and Results— Using real-time polymerase chain reaction, we quantified mRNA for different forms of Fas and for FasL. In resting lymphocytes, mRNA for tFas, but not for mFas, significantly increases with age, whereas FasL mRNA significantly decreases. In vitro production of Fas/FasL mRNA after different stimuli was similar in cells from the 3 groups. Even if the percentage of Fas⁺ cells was higher than in the other groups, peripheral blood lymphocytes from centenarians had normal Fas-induced apoptosis, as revealed by flow cytometry. By ELISA, we observed that cells from centenarians showed normal in vitro production of the soluble form of Fas (sFas) and that plasma levels of such molecule were significantly higher in centenarians than in the other groups.

Conclusions— Lymphocytes from centenarians are able to balance the production of proapoptotic (mFas and FasL) and antiapoptotic (sFas) molecules, whose proportions are likely crucial for the well-preserved immune functionality at the extreme limits of human life.

Key Words: aging • apoptosis • immune system • lymphocytes

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