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Aging Research in Immunology (ARIG):
Impact of Genomics
Janko Nikolich-Zugich, MD, PhD
The meeting
“Aging Research in Immunology (ARIG):
Impact of Genomics” (www.arig.ac.at)
was held in Paris on September 4 - 5,
2006, with the support of European
Economic Commission and the NIH. This
was the first trans-Atlantic meeting
devoted solely to the studies of immune
senescence, and as such it brought
together an impressive lineup of experts
in the aging of the immune system
(please see the website for the list of
participants and speakers). The meeting
compressed into two days the entire
palette of immunology of aging:
lymphocyte development, homeostasis,
turnover and effector cell function,
innate and adaptive immunity, genetics,
genomics and proteomics, in a spectrum
of different experimental models. Due to
the limited space, this overview will
only provide the summary of discussions
and findings, without attributing them
to individual speakers. Those interested
in a more detailed overview, with
speaker attributions, should read the
recent article by G. Pavelec in EMBO
Reports online (in press).
Age-related problems were reported in
virtually every facet of innate and
adaptive immunity, starting with
lymphocyte development. Hematopoietic
stem cells (HSC) are not numerically
decreased in old animals, yet seemed
less able on a per-cell basis to produce
progeny, and that progeny differed from
that produced by adult HSC. This
correlated well with recent findings
that lymphocyte, but not myeloid,
development may be particularly
strongly affected by aging. Indeed, a
multitude of age-related defects were
reported in both B and T-cell
development, at a cell-autonomous level
as well as in the old microenvionment.
IL-7 was again implicated in
developmental defects, this time in B
cells, and it and other cytokines
important for lymphocyte survival (IL-7
and IL-15 for T and BLys/BAFF for B
cells) were found to be dysregulated. It
is not clear how this impacts lymphocyte
competition for survival, given that
decrease in production of new T and B
cells in aging may lower the bar for
survival of fit (and unfit) cells.
Another critical issue that is beginning
to be addressed is that of regulation of
immune responses in this dysregulated
environment – new evidence was reported
that prolonged responses may dominate in
the old. It will be critically important
to elucidate whether this is also
because there is reduced antigen
elimination, conducive to chronic or
prolonged stimulation of lymphocytes.
This theme has been further extended by
elegant human T-cell turnover studies,
showing that CD8 memory T-cells exhibit
a much longer half-life than any other
subset in the elderly, mostly through a
combination of low-level proliferation
and long-term persistence. Antigen
role in maintaining clonal expansions of
CD8 T-cells was discussed, and the role
of homeostatic forces, as well as of
persisting and acute infectious agents,
was demonstrated. Apoptosis resistance
was also implicated in the accumulation
of these cells, as was altered
responsiveness to cytokines. The
interplay of these factors and the key
and primary players should now be
identified through further studies.
Age-associated changes were also found
in the cells of the inflammatory /
innate immune system, including
alterations in NKT cell subsets; in
neutrophils, which with age retained
many normal functions (e.g. chemotaxis
and superoxide generation) but were
inferior in phagocytosis, and appeared
to secrete more IL-6, a pro-inflammatory
cytokine which correlated to higher
susceptibility to infection in burn
trauma animals; and in dendritic cells
(DC), which connect innate to adaptive
immunity, and which showed age-related
defects in chemotaxis and phagocytosis.
DC from the elderly also exhibited
specific defects in stimulation of CD4,
but not CD8 T-cells, an effect that
beckons further studies into the
age-related changes in biochemistry of
antigen processing and presentation, as
well as DC activation.
Many of these changes contribute to
reduced pathogen clearance and
resistance, but there is a consensus
that abnormalities in T-cell repertoire
and memory maintenance in that regard
probably play a decisive role. Thus,
influenza virus elicited a slow and
reduced cytotoxic T-lymphocyte (CTL)
response, and that was accompanied by
delayed clearance of the virus from the
lungs of old mice. This could be caused
in part by failure to "make space" for
the response to new pathogens in old
mice, perhaps due to the accumulation of
memory cells (the clonal expansions
referred to above) which were found to
be resistant to non-specific depletion
in old, but not young, animals.
Moreover, it is clear that a diverse
TCR repertoire is critical to the
response to new antigens (pathogens),
and evidence is accumulating that
repertoire attrition and high levels of
peripheral cell turnover are bad
prognostic signs in the elderly.
Telomeres as well as the expression of
telomerase were used to study possible
exhaustion of proliferative capacity in
aging and chronically stimulated T
cells, leading to attrition of TCR
repertoire, and there were reports on
the potential use of the catalytic
component of telomerase, hTERT, to
extended lifespan and function of
chronically stimulated T cells in vitro.
It is yet unclear whether this can be
applied to aged cells as well.
In humans, longitudinal studies of the
very elderly (> 85 yr) have revealed an
over-riding association of persistent
CMV and the repertoire attrition.
Furthermore, the number of different
CMV-specific clonal expansions was found
to be a risk factor predicting
mortality. The CMV-specific CD8 clones
which accumulate contain functional
cells (producing IFN-g on specific
stimulation) and a larger fraction of
dysfunctional cells (anergic). Similar
expansions can be seen in HSV-1-infected
mice, and they tend to accumulate with
age in a manner suggesting persistent
antigenic stimulation. In the absence
of manifest infection, age-associated
alterations of TCR diversity may
manifest themselves over very short time
periods, and the proposal was made that
"catastrophic events" such as another
drastic drop in the output of new T
cells from the thymus, may precipitate
those changes.
The meeting devoted several talks to
possible corrective interventions. New
vaccines, adjuvants, the restorative
interventions and caloric restriction
were all discussed. The key issue is
whether there is enough of the naïve T
cell reserve to obtain functional
responses after vaccination or whether
regeneration of the T cell compartment
should be attempted first. In the former
case. pro-inflammatory cytokines (IL 1,
IL 6 and TNF-a) effectively promoted CD4
helper function in old mice, but
restoration of CD4 T-cells by
regeneration, presumably from the old
thymus, was also very effective.
Similarly, caloric restriction in
monkeys helped maintain naïve T-cells,
preserve TCR repertoire diversity and
gene expression patterns at youthful
levels. The problem in some elderly
humans may be that there are too few
naïve cells remaining that could be
targeted by adjuvants, because CD8 cells
with an apparently naïve phenotype
(CD45RA+ CD28+) already show many signs
of senescence. A major challenge for the
future will be to discriminate between
those states of senescence that require
different therapeutic approaches by
using reliable biomarkers, and to devise
treatments and vaccine formulations
tailored to the use in immune aging.
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MEETING ANNOUNCEMENTS
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March 30 - 31,
2007
The Edmonton Aging Symposium
Sponsored
by: The Methuselah Foundation,
University of Alberta,
City of Edmonton
Edmonton, Alberta,
Canada
A thought
provoking two days that involves presentations
which examine the economic and ethical
justifications for the development of
technologies capable of extending the human
lifespan as
well as evidence provided by top
researchers in the fields of stem cells, tissue
engineering, cancer therapies, neurodegeneration
and others, that
demonstrates these technologies are possible and
under development. Poster submissions accepted
until March 15, 2007. Cash prizes for best
posters in biomedical and social sciences. Roundtable
scientific and ethical panel discussions are
being held with open participation but space is
limited.
www.edmontonagingsymposium.com
April 17-20, 2007
Alzheimer's Disease: From Molecular Mechanisms
to Drug Discovery
Punta Cana,
Dominican Republic
The aim of the
meeting is to provide an update on the current
basic mechanisms involved in the pathogenesis of
Alzheimer's disease and the applicability of
novel drug discovery approaches to treat
it.
www.worldeventsforum.com/ad
May 16-19, 2007
Diet and Optimum Health Conference
Linus Pauling Institute
Portland, Oregon
Diet and Optimum Health 2007 will emphasize the
prevention and treatment of human diseases by
lifestyle and diet modifications. The target
audience for the conference includes scientists
and health professionals in preventive medicine,
public health, clinical nutrition, cardiology,
and oncology. We anticipate a strong scientific
look at the cutting edge of nutrition research.
http://lpi.oregonstate.edu/conf2007/
7-8 June, 2007
Alzheimer's Disease Biomarkers
Washington, DC, U.S.A.
Academic and corporate scientists will discuss
the state-of-the-art in Alzheimer biomarkers
research and explore how studies of various
populations might be used to advance the
development of antecedent biomarkers for disease
diagnosis and drug discovery. Speakers will
focus on the applications of genetics, imaging,
metabolomics, biochemistry, and pharmacogenomics
in research involving familial Alzheimer
disease, Down syndrome, adult children studies,
and existing longitudinal studies of normal
aging. The program will include a poster session
encompassing both traditional and
non-traditional biomarkers of AD.
www.hcnr.med.harvard.edu/biomarkers.php
September 6-10,
2007
Strategies for Engineered Negligible Senescence
(SENS), 3rd Conference
Cambridge,
United Kingdom
The purpose of the SENS conference series is
to expedite the development of truly effective
therapies to postpone and treat human aging by
tackling it as an engineering problem.
www.sens.org/sens3/
September 28-29, 2007
6th Leonard Berg Symposium: Novel Therapies for
Protein Misfolding Disorders
Washington University St. Louis
alzheimer.wustl.edu/Education/Berg/Berg2007/PresentPoster.htm
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