immune aging manifests itself at several levels , from the whole organism to individual cells . at the organismal level , morbidity and mortality from numerous viral ( influenza , varicella - zoster , herpes simplex virus-1 , and poxviruses ) and bacterial ( pneumococci ; escherichia coli , salmonella ) diseases , including some notable emerging pathogens ( west nile virus [ wnv ] and sars - inducing coronavirus ) is increased in elderly humans and old animals ( for review see references 13 ) . these pathogens use distinct ports of entry and induce distinct pathologies that affect numerous organ systems ( such as the skin , respiratory , circulatory , urinary , central nervous system , etc . ) , suggesting a decline and dysregulation of many processes that normally lead to effective immunity ( 1 , 2 ) . although it is likely that functional and structural alterations in both the entry sites and the target organs used by these pathogens facilitate age - related susceptibility to some infections ( for example , impaired barrier function ) , there is no doubt that the dysregulation of immunity also plays a central and critically important role in this process . accordingly , responsiveness to vaccination in the elderly is also substantially diminished , and vaccine - induced protection is suboptimal . at the cell population level , involution of the primary lymphoid organs and defects in the production of early lymphoid precursors even the generation of the earliest defined lymphoid precursors is diminished in aging ( for review see references 4 and 5 ) . the other decisive factor is the lifelong encounter of the immune system with both acute and chronic pathogens . recent evidence suggests that persisting pathogens are very important in modulating the numbers , function , and homeostasis of t cell subsets as they result in an ever increasing fraction of t cells that are continuously or intermittently stimulated ( for review see reference 6 ) . finally , at the individual cell level , the fundamental processes affected by aging include both the innate and adaptive arms of the immune response . specifically , macrophage activation , dc migration , follicular dc function , and toll - like receptor  mediated activation were all found to be impaired or dysregulated to some degree ( for review see references 5 and 7 ) . likewise , antigen presentation , although still insufficiently investigated , has been reported to be decreased ( 8) . constitutive cytokine secretion is generally regarded as elevated , whereas that in response to antigen or pathogen stimulation is generally reduced ( 9 ) . specifically , interleukin ( il)-2 secretion by stimulated naive t cells is reduced , and there is dysregulation of both nonimmune and immune interferon and il-6 production . b cell and , in particular , t cell function is heavily altered . germinal center formation is reduced , antibody responses are delayed and blunted , and antibody affinity ( and affinity maturation ) is impaired ( for review see reference 10 ) . similarly , t cell receptor and costimulatory signaling pathways are blunted , secretion of some cytokines ( chiefly il-2 ) by stimulated naive t cells is drastically reduced , and there is an accumulation of nonfunctional , possibly replicatively senescent t cells ( for review see references 1 , 4 , and 11 ) . some of the defects in aging t cells are listed in table i. some of the known or suspected defects in t cell senescence presently , our understanding of the mechanisms leading to immune aging remains incomplete . nevertheless , major advances made in the last couple of years , including two new studies by eaton et al . ( 13 ) , have helped define many of the age - related defects in the t and b cell compartments . one of these studies showed that in response to nitrophenyl - pigeon cytochrome c , defects in t cell cognate help primarily and dominantly affect b cell immunity in old mice , and that transfer of young t cells into aged mice largely normalizes antibody production ( 12 ) . transfer of old t cells into young animals yielded poor b cell responses and one suspect in this decline appears to be diminished expression of cd40 ligand ( 12 ) . although this stresses the importance of t cell senescence and although i will continue to discuss t cells in the remainder of this article , one should be mindful that other primary defects upstream of t cells may very well exist and be very important . t cells can sense the presence or the absence of sufficient numbers of other t cells around them and adjust their division rate and numbers accordingly . thus , in a lymphopenic situation , massive proliferation of existing ( or transferred ) t cells occurs to compensate for the low number of preexisting t cells . once the cell numbers reach a given level , the signal for proliferation is likely exhausted or turned off , and proliferation is terminated . i shall discuss naive and memory t cell homeostasis separately ( 14 ) in further deliberations , although the two compartments may not be as independent as previously believed ( at least cd8 memory t cells seem to cross - inhibit proliferation and/or repopulation of the periphery by naive cells ; references 5 and 15 ) . in a steady - state situation , where new ( naive ) t cells are constantly produced by the thymus , murine recent thymic immigrants ( rte ) populate the periphery and are exempt from competition with the preexisting naive t cell pool for about 3 wk ( 16 ) . given the estimated rate of 2  10 rte / day in a mouse , the same number of t cells needs to be lost on a daily basis to make space for the newcomers . moreover , as the rte proliferate in the periphery , it is likely that more cells need to be lost from the preexisting pool . most , if not all , cells dying in this situation would also be naive . otherwise , the rest of the naive pool divides very slowly until ( and unless ) stimulated by a cognate antigen or by a lymphopenic environment . memory t cells , by contrast , are self - renewing in the periphery and their active cycling ( about once a week ) is offset by an equivalent cell loss from the memory t cell subset . t cell receptor ( tcr ) stimulation ( for naive cells at least ) and the cytokines il-7 and il-15 ( for both naive and memory cells ) provide critically important trophic signals that maintain viability and division rate , although some aspects of this regulation remain under investigation ( for review see reference 15 ) . in an empty or partially depleted compartment , both memory and naive t cells sense the void and begin proliferating , again driven by signals from the tcr , il-7r , and il-15r ( for review see reference 15 ) . this homeostatic proliferation stops once t cells fill the compartment . in the most simplistic sense , filling and emptying of t cell compartments at a molecular level could simply mean sensing a surplus or a relative lack of the homeostatic cytokines il-7 and il-15 . regardless of the exact molecular meaning of the void , changes in supply and demand of naive t cells set the stage for the most profound changes in aging . thymic production declines at least 10-fold by the time of puberty ; therefore , fewer naive rte will mean higher proliferation of the remaining naive t cells . meanwhile , these naive t cells are being depleted over a lifetime of encounters with acute and , even more importantly , chronic persisting pathogens . this leads to a lifelong accumulation of memory cells that appear to be well preserved in aging ( 5 , 17 , and unpublished data ) and that may impair repopulation and/or homeostatic proliferation by naive cells ( 5 and unpublished data ) . simultaneously , il-7 levels could be reduced with age ( 18 ) , potentially affecting maintenance and viability of naive cells . il-2 production is diminished and this cytokine is critically important in the elimination of expanded t cells in the contraction stage of the immune responses ( 19 ) , potentially leading to further accumulation of memory cells . it is therefore not surprising that the naive to memory t cell ratio decreases , often severely , with aging . accordingly , the glass ( the naive t cell compartment ) looks worse than half - empty from that perspective . that the glass is actually at least half - full is a testament to the resilience of t cell homeostasis . in fact , the situation would be utterly dismal were it not for the homeostatic and compensatory mechanisms that ensure normal function of t cells into adulthood and early senescence . at present , we do not possess quantitative information on just how elastic and active these mechanisms really are . thus , lymphocytes can divide many times in response to antigen and in response to homeostatic stimuli , and although these cells are equipped with mechanisms to allow for intense division ( for example , the induction of telomerase ; reference 20 ) , that capacity may not be infinite ( 11 ) . in principle , there is either a limit to the number of divisions that each cell can undergo , or the stochastic accumulation of mutations after n divisions ( with n being highly variable even within the cells of the same clone ) simply produces replicatively incompetent cells . regardless , it is expected that at some point homeostatic proliferation will not be able to compensate for the lack of new t cell production and for their lifelong depletion . again , this point can be viewed from the perspective of a single cell , cell populations , or the whole organism . in humans , the age of 65 is usually taken as the beginning of senescence , as this is when the incidence of severe infectious diseases becomes elevated . however , with many pathogens , increased sensitivity occurs earlier ( for example , wnv and sars , where increased vulnerability starts at , or slightly before , the age of 50 ) . in an attempt to measure the chronological breakdown of homeostasis , goronzy 's group recently tested thymic function , lymphocyte turnover , and t cell repertoire in humans throughout middle and old ages ( unpublished data and reference 5 ) . their results suggest that discrete time points mark specific events that lead to a breakdown of homeostatic control in the cd4 t cell pool . although there is a log linear decline in thymic output during middle age ( 2060 yr ) , intense compensatory proliferation of the remaining naive cd4 , and a final  catastrophic loss  of naive cd4 t cells with drastic repertoire constriction , typically occurs in the seventh decade . if confirmed , these stages would mark periods during which important measurements can be taken to elucidate the basis of each event , and also during which different interventions can be tested . other adverse consequences of compensation for naive t cell loss occur at the level of cell populations and individual cells . one is the accumulation of cells with a poor ability to replicate in response to antigen , and these seem to be particularly prone to arise in response to chronic persistent infections ( 11 , 21 ) . moreover , cell division is one of the main causes of mutations , which can lead to cancer ( 22 ) or to less severe transformation as in the case of t and b cell clonal expansions ( 23 , 24 ) . these transformed cells take up space at the expense of other t cells , leading to a drastic reduction in t cell repertoire diversity . recent evidence suggests that they are part of a vicious circle that can lead to impaired immune responses ( 25 ) . therefore , compensatory homeostatic mechanisms perform critical functions but are also eventually exhaustible , as witnessed by their association with new risks of malfunction and disease ( 6 , 25 ) the recent plethora of information on t cell homeostasis has raised numerous questions regarding aging of t cell compartment , one of which was elegantly answered in this issue by haynes et al . these authors asked , if naive cells can divide many times and remain naive for many years , are they different from cells that arise in an old organism but are young as measured by the time since their egress from the thymus ? can , in fact , newly generated t cells be functional in old mice ? using antibody - mediated depletion and/or bone marrow chimeras , the authors showed that newly generated t cells in old mice apparently function normally and mount vigorous responses to primary immunization . the results were confirmed in both the tcr transgenic and wild - type mouse models , adding physiological relevance to this important observation . if confirmed , these results would bode well for the attempts to increase thymic production and/or improve survival and maintenance of naive t cells ( for review see reference 26 ) . at this point , however , there are many outstanding questions stemming from this work . for is there a barrier to the influx of new t cells imposed by old t cells or old microenvironment in the reconstituted animal ? although the new cells were shown to function well , are they equal to the ones in young animals with regard to immune defense ( for example , do they protect equivalently in a challenge experiment ) ? answering these questions will be both interesting and challenging , and , along with testing of other experimental treatments , should pave way to targeted therapies for immunosenescence in the intermediate and long term . the above discussion stresses the necessity to identify ways to ameliorate and treat the underlying causes of immunosenescence . table ii lists a few examples of studies addressing cellular and molecular basis of selected treatments to improve t cell function treatments aimed at improving thymic output and/or function are reviewed in references 4 , 26 , and 27 . unfortunately , there are very few treatments that are both clinically applicable and efficacious , mandating additional research efforts to improve this outlook . manipulation of cytokines critical to t cell homeostasis ( il-7 and il-15 ) is likely to be high on that list . selected experimental treatments to improve t cell immune function in aging an overlapping and concurrent but separate line of research is aimed at improving immune responses to vaccination in the elderly population . a fundamental question whether some vaccines need to be reengineered , and whether others can be modified , still needs to be answered . improvement of cd4 t cell function with the use of adjuvants has shown some promise in rodents ( 31 ) , however translation of these findings into humans is uncertain . similarly , supplementing vaccines with dna constructs encoding cytokines and/or costimulatory molecules can improve results of priming in adult mice , but that strategy has shown little promise in humans due to problems with both the delivery methods and differences between mice and humans . regardless , il-12 and il-18 appear to be the prime candidates for vaccine optimization . another strategy would be to optimize recognition of vaccine components by the innate immune system . for such strategies to be effective , however , it will be important to dissect the most important and the primary points of intervention and the extent to which these points can be influenced , allowing us to rationally design treatments and vaccines for the elderly .
the immune system exhibits profound age - related changes , collectively termed immunosenescence . 
 the most visible of these is the decline in protective immunity , which results from a complex interaction of primary immune defects and compensatory homeostatic mechanisms . 
 the sum of these changes is a dysregulation of many processes that normally ensure optimal immune function . 
 recent advances suggest that old mice can produce fully functional new t cells , opening both intriguing inquiry avenues and raising critical questions to be pursued .