February 05, 2011

SENS looks at rejuvenating immunity through ablation

The degenerative aging of the immune system is responsible for an enormous burden of disease and disability, from the pain of recurrent Herpes zoster and postherpetic neuralgia, to elevated rates of chronic urinary tract infections, to complications in wounds, pressure sores, ulcers, and surgical incisions. Most prominently, it underlies the meteoric rise in mortality from respiratory infections with age: influenza, pneumonia, and septicemia rise from being negligible causes of death in healthy middle-aged adults in the USA, to emerge amongst the top 10 causes of death in adults over the age of 55, with mortality rates climbing with each successive year of aging. And in addition to increasing the morbidity and mortality specifically attributable to particular infections, the dysregulation of immune function by immunosenescence is widely acknowledged to exacerbate multiple chronic age-related illnesses, and to contribute to functional decline and frailty in aging people

Note: also there has been work that suggests that super-strengthening of the immune system could be paths to curing cancer and HIV Aids.

The solution to age-related suffering and death from specific infections, autoimmunity, and inflammation is the application of rejuvenation biotechnology to the aging immune system itself.

The clearest and longest-established contributor to immune senescence is the decline in adaptive immunity mediated by T lymphocytes, the biomedical remediation of which has therefore been the focus of SENS Foundation's investments in immunological rejuvenation research. The existence, nature, and causes of age-related deficits in B-cell structure and function have long been less clear, but emerging evidence has recently led to a consensus of their reality, although the mechanisms have not yet been definitively established. Among the key questions are whether and to what degree this decline in humoral immunity attributable to the degenerative aging process is mediated through the introduction of intrinsic defects to the B-cells themselves, vs. alterations in the systemic environment of the aging body. The strategy for the development of rejuvenation biotechnology for this arm of the aging immune system will be determined by the answers to these questions.

Now, a conceptually simple single experiment performed by Doron Melamed and colleagues at the Technion-Israel Institute of Technology has simultaneously provided powerful evidence for the existence of intrinsic defects in an accumulating population of long-resident B-cells in biologically aged hosts, and for a relatively straightforward intervention to substantially restore youthful humoral immunity in such organisms.

Melamed's group studied the effects of the degenerative aging process on B-cell function using young adult (4 mo) and early-old (20 mo)
C57JBl/6 mice. Several models were used to evaluate the possible role of accumulations of long-extant peripheral B cells with age in suppressing B-cell lymphopoiesis and contributing the the overall levels of cell-intrinsic defects in the aging organism's B-lymphocyte population. One such model was transgenic (TG) mice with an inducible Cre/lox system allowing for conditional knockout of the gene encoding the receptor for B-Cell Activation Factor Receptor (Baff-r). Baff-r is a B-cell activation factor in the tumor necrosis factor (TNF) family whose signaling is essential for the survival of mature B lymphocytes, but is conveniently dispensable for generation of new ones. Activation of the recombinase system allowed the investigators to rapidly deplete animals of B-cell populations that had developed, matured, and aged normally. In additional experiments, the Israeli group further confirmed and expanded their findings in Baff-r-TG mice with similar B-cell depletion studies in aging wiltd-type (WT) mice subjected to depleting antibody mixture, and to the targeting of transgenic human CD20 in hCD20-TG mice.

It remains to be demonstrated that this apparent rejuvenation effect extends to a gold-standard test of greater survival from infectious disease in treated animals. If that can be convincingly shown, then discovering the reasons for the remaining limits on B-cell function in animals treated with B-cell depletion will be important to further the progress to this research, and to using the proof-of-principle that the Israel-Technion team appears to have provided to develop intervention protocols suitable not only for animal testing, but for translation into rejuvenation therapies for aging humans.

Another question is how these new findings integrate with prior research on the aging haematopoietic system. Previous work has shown the role of the deranged signaling environment of the biologically aged organism in repressing non-immune functions of the haematopoietic stem cell niche, and the rejuvenation of the HSC niche by a youthful systemic environment. Other research has highlighted the role of intrinsic defects in the degenerative aging process of HSCs, and the ability of the autophagy-enhancing (and, in mice, life-extending) drug rapamycin to partially restore immune function in aging mice. The combination of this research on the systemic, cell-intrinsic, and population influences on degenerative aging of B-lymphocyte functions, and the many interventions already shown to partially rejuvenate aspects of it, gives significant grounds for optimism that interventions can be developed to effect a protocol -- or combination of protocols -- to effect the thoroughgoing rejuvenation of haematopoietic aging, and on timescales that many in the field might until recently have thought unrealistic.

For some time, SENS Foundation's research investments in immune rejuvenation have been centered on T-cell function, dedicated to the complementary strategies of engineering youthful thymic epithelium to restore youthful production of naïve T-cells, and ablation of anergic T-cells to open up the immunologic 'space' required for their expansion. The finding that depletion of long-resident B-lymphocytes leads to a partial rejuvenation of B-cell precursor content, lymphopoieisis, and antibody production is an unexpected and striking parallel to the expected effects of ablating anergic T-cells. This new research strongly confirms the expectation that a comprehensive strategy of rejuvenation biotechnologies will need to include both arms of the adaptive immune system, and strongly suggests key features of the tools that will be needed to do so.

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