Roy Walford and the immunologic theory of aging

Roy Walford died on April 27, 2004, at the age of 79. His contributions to gerontological research in such diverse areas as caloric restriction, genetics of lifespan, immunosenescence, DNA repair and replicative senescence were truly remarkable in their depth and innovation. Significantly, most of the areas that he pioneered during his illustrious research career remain the "hot" areas of current gerontological research. In this sense, he has achieved the most important type of immortality. His death was a major personal and professional loss to numerous scientists within the gerontological community. In launching this new journal on Immunity and Ageing, it is highly fitting, therefore, to remember him on the anniversary of his death by briefly reviewing the contributions of Roy Walford to this important facet of gerontology. Indeed, it was Roy who actually first coined the commonly used term "immunosenescence"

Prostaglandin E2 promotes features of replicative senescence in chronically activated human CD8+ T cells.

Prostaglandin E2 (PGE2), a pleiotropic immunomodulatory molecule, and its free radical catalyzed isoform, iso-PGE2, are frequently elevated in the context of cancer and chronic infection. Previous studies have documented the effects of PGE2 on the various CD4+ T cell functions, but little is known about its impact on cytotoxic CD8+ T lymphocytes, the immune cells responsible for eliminating virally infected and tumor cells. Here we provide the first demonstration of the dramatic effects of PGE2 on the progression of human CD8+ T cells toward replicative senescence, a terminal dysfunctional state associated multiple pathologies during aging and chronic HIV-1 infection. Our data show that exposure of chronically activated CD8+ T cells to physiological levels of PGE2 and iso-PGE2 promotes accelerated acquisition of markers of senescence, including loss of CD28 expression, increased expression of p16 cell cycle inhibitor, reduced telomerase activity, telomere shortening and diminished production of key cytotoxic and survival cytokines. Moreover, the CD8+ T cells also produced higher levels of reactive oxygen species, suggesting that the resultant oxidative stress may have further enhanced telomere loss. Interestingly, we observed that even chronic activation per se resulted in increased CD8+ T cell production of PGE2, mediated by higher COX-2 activity, thus inducing a negative feedback loop that further inhibits effector function. Collectively, our data suggest that the elevated levels of PGE2 and iso-PGE2, seen in various cancers and HIV-1 infection, may accelerate progression of CD8+ T cells towards replicative senescence in vivo. Inhibition of COX-2 activity may, therefore, provide a strategy to counteract this effect

AF-algebras and topology of mapping tori

A covariant functor from the category of mapping tori to a category of AF-algebras is constructed; the functor takes continuous maps between such manifolds to stable homomorphisms between the corresponding AF-algebras. We use this functor to develop an obstruction theory for the torus bundles of dimension 2, 3 and 4.Comment: to appear Czechoslovak Math.

Decreased perforin and granzyme B expression in senescent HIV-1-specific cytotoxic T lymphocytes

AbstractCytotoxic T lymphocyte (CTL) senescence may be an important mechanism of immune failure in HIV-1 infection. We find that senescence of HIV-1-specific CTL clones causes loss of killing activity, preventable by transduction with telomerase. Furthermore, senescence is associated with reduced expression of the effector molecules granzyme and perforin, suggesting CTL “exhaustion” can result in hypofunction. These results agree with other studies showing that HIV-1-specific CTL exhibit abnormal phenotypes in vivo, and suggest the possibility that chronic turnover is an important mechanism of antiviral failure in HIV-1 infection

Structure, classifcation, and conformal symmetry, of elementary particles over non-archimedean space-time

It is known that no length or time measurements are possible in sub-Planckian regions of spacetime. The Volovich hypothesis postulates that the micro-geometry of spacetime may therefore be assumed to be non-archimedean. In this letter, the consequences of this hypothesis for the structure, classification, and conformal symmetry of elementary particles, when spacetime is a flat space over a non-archimedean field such as the $p$-adic numbers, is explored. Both the Poincar\'e and Galilean groups are treated. The results are based on a new variant of the Mackey machine for projective unitary representations of semidirect product groups which are locally compact and second countable. Conformal spacetime is constructed over $p$-adic fields and the impossibility of conformal symmetry of massive and eventually massive particles is proved

Multiplicativity of completely bounded p-norms implies a new additivity result

We prove additivity of the minimal conditional entropy associated with a quantum channel Phi, represented by a completely positive (CP), trace-preserving map, when the infimum of S(gamma_{12}) - S(gamma_1) is restricted to states of the form gamma_{12} = (I \ot Phi)(| psi >< psi |). We show that this follows from multiplicativity of the completely bounded norm of Phi considered as a map from L_1 -> L_p for L_p spaces defined by the Schatten p-norm on matrices; we also give an independent proof based on entropy inequalities. Several related multiplicativity results are discussed and proved. In particular, we show that both the usual L_1 -> L_p norm of a CP map and the corresponding completely bounded norm are achieved for positive semi-definite matrices. Physical interpretations are considered, and a new proof of strong subadditivity is presented.Comment: Final version for Commun. Math. Physics. Section 5.2 of previous version deleted in view of the results in quant-ph/0601071 Other changes mino

Sustained CD28 Expression Delays Multiple Features of Replicative Senescence in Human CD8 T Lymphocytes

CD28 costimulatory signal transduction in T lymphocytes is essential for optimal telomerase activity, stabilization of cytokine mRNAs, and glucose metabolism. During aging and chronic infection with HIV-1, there are increased proportions of CD8 T lymphocytes that lack CD28 expression and show additional features of replicative senescence. Moreover, the abundance of these cells correlates with decreased vaccine responsiveness, early mortality in the very old, and accelerated HIV disease progression. Here, we show that sustained expression of CD28, via gene transduction, retards the process of replicative senescence, as evidenced by enhanced telomerase activity, increased overall proliferative potential, and reduced secretion of pro-inflammatory cytokines. Nevertheless, the transduced cultures eventually do reach senescence, which is associated with increased CTLA-4 gene expression and a loss of CD28 cell surface expression. These findings further elucidate the central role of CD28 in the replicative senescence program, and may ultimately lead to novel therapies for diseases associated with replicative senescence

Relative commutants of strongly self-absorbing C*-algebras

The relative commutant $A'\cap A^{\mathcal{U}}$ of a strongly self-absorbing algebra $A$ is indistinguishable from its ultrapower $A^{\mathcal{U}}$. This applies both to the case when $A$ is the hyperfinite II$_1$ factor and to the case when it is a strongly self-absorbing C*-algebra. In the latter case we prove analogous results for $\ell_\infty(A)/c_0(A)$ and reduced powers corresponding to other filters on $\bf N$. Examples of algebras with approximately inner flip and approximately inner half-flip are provided, showing the optimality of our results. We also prove that strongly self-absorbing algebras are smoothly classifiable, unlike the algebras with approximately inner half-flip.Comment: Some minor correction