Interestingness: 4
By Izumi Horikawa, Toshio Yawata, and J Carl Barrett in the Journal of Anti-Aging Medicine, Volume 3, Issue 4, 2000 (pp 373-382, doi:10.1089/rej.1.2000.3.373.)
Not all cells given telomerase escape senescence and cells with active telomerase can be made to senesce in lots of ways. The p16INK4A/RB pathway can trigger senescence as well as the p14ARF/MDM2/p53 pathway. p53 is probably related to telomeres but other parts probably aren't. By introducing single chromosomes into immortal cancer cell-lines and making them senesce, they infer the existence of other independent pathways of senescence. The mechanisms that trigger senescence are cell-type dependent.
Interesting factoid: mouse cells senesce after much fewer replications (10-20 vs 50-80) even though much longer telomeres.
Showing posts with label senescence. Show all posts
Showing posts with label senescence. Show all posts
Thursday, December 29, 2011
Monday, April 4, 2011
Role of Cell Senescence in Human Aging
Summary: Cell senescence is the problem, but we won't talk about cancer.
Interestingness: 7
Paper by Michael Fossel in the Journal of Anti-Aging Medicine, Volume 3, Issue 1, Spring 2000.
(((
This paper is mostly a defense of the senescence model of aging which consists of saying that cell senescence is the main reason for aging. The paper consists of clarifications on possible misinterpretations of the theory. The model, it says, only pertains to human aging. It says that in critical tissue, enough cells senesce for it to have organism-wide effects, either by their inability to replicate, or by their changed gene expression patterns.
The clarifications are presented by examples. One main example is that heart attacks and strokes are compatible with the theory. Damage to the endothelial cells, the surface layer, cause neighbouring endothelial cells to replicate. At some point they senesce, at which point the holes on the surface aren't fixed any more and the plasma has direct access to the subendothelial layer, triggering the rest of the effects. A bit of supporting evidence is that the places on the blood vessels at which atherosclerosis is usually formed are the same places at which telomere length of endothelial cells is shortest.
The paper has doubts about the ability of the model to explain Alzheimer's but it suggests that since astrocytes divide, measuring telomere length in astrocytes and comparing to Alzheimer's propensity would be a good test.
There is an interventionist undertone to the paper, which is why I think it is interesting. It wants to shove human telomerase (hTERT) in tissue (leukocyte stem cells, the skin of Hutchinson Gilford Syndrome patients, arterial endothelial cells) and see if that fixes them or affects longevity. It mentions unpublished experiments, at least unpublished at that time, about using young cells vs old cells vs old cells with telomerase, in forming skin layers on a naked mouse. The old cells formed skin that looked like old human skin, while the young and telomerased cells formed normal, "grossly, microscopically and genetically", looking skin.
I am a bit surprised that the paper doesn't mention cancer at all. Senescence seems like a method of cancer control so I'd expect something to be said about it. The theory is vague and broad enough to be compatible with lots of other theories of aging, but I think it is not compatible with the mitochondrial free radical theory of aging. The one presented here seems easier to test.
)))
Interestingness: 7
Paper by Michael Fossel in the Journal of Anti-Aging Medicine, Volume 3, Issue 1, Spring 2000.
(((
This paper is mostly a defense of the senescence model of aging which consists of saying that cell senescence is the main reason for aging. The paper consists of clarifications on possible misinterpretations of the theory. The model, it says, only pertains to human aging. It says that in critical tissue, enough cells senesce for it to have organism-wide effects, either by their inability to replicate, or by their changed gene expression patterns.
The clarifications are presented by examples. One main example is that heart attacks and strokes are compatible with the theory. Damage to the endothelial cells, the surface layer, cause neighbouring endothelial cells to replicate. At some point they senesce, at which point the holes on the surface aren't fixed any more and the plasma has direct access to the subendothelial layer, triggering the rest of the effects. A bit of supporting evidence is that the places on the blood vessels at which atherosclerosis is usually formed are the same places at which telomere length of endothelial cells is shortest.
The paper has doubts about the ability of the model to explain Alzheimer's but it suggests that since astrocytes divide, measuring telomere length in astrocytes and comparing to Alzheimer's propensity would be a good test.
There is an interventionist undertone to the paper, which is why I think it is interesting. It wants to shove human telomerase (hTERT) in tissue (leukocyte stem cells, the skin of Hutchinson Gilford Syndrome patients, arterial endothelial cells) and see if that fixes them or affects longevity. It mentions unpublished experiments, at least unpublished at that time, about using young cells vs old cells vs old cells with telomerase, in forming skin layers on a naked mouse. The old cells formed skin that looked like old human skin, while the young and telomerased cells formed normal, "grossly, microscopically and genetically", looking skin.
I am a bit surprised that the paper doesn't mention cancer at all. Senescence seems like a method of cancer control so I'd expect something to be said about it. The theory is vague and broad enough to be compatible with lots of other theories of aging, but I think it is not compatible with the mitochondrial free radical theory of aging. The one presented here seems easier to test.
)))
The notion that cell senescence might, ultimately, be central to human aging has been attractive but unsubstantiated for the past four decades. Recent genetics and cell biology work has strongly supported this position. The model has been criticized, largely because few understand what the model actually says about aging. The cell senescence model (often mislabeled the "telomere theory of aging") suggests that changes in gene expression within senescent cells underlie most common age-related pathology, for example those occurring in the coronary arteries in atherosclerosis. It does not suggest that most somatic cells senesce, but rather that those cells which do senesce (e.g., endothelial cells, chondrocytes, fibroblasts, keratinocytes, microglia, hepatocytes, etc) are common denominator of human aging and age-related disease as well as the most efficient point for therapeutic intervention. The cell senescence model of human aging remains elegant and consistent with all known data on human aging and disease; an appropriate criticism is that it remains yet unproven.
Sunday, October 24, 2010
Importance of T-Cell Replicative Senescence for the Adoptive Immunotherapy of Cancer in Humans?
Summary: Review of replication of T-cells in vitro
Interestingness: 3
Paper by Graham Pawelec in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.
(((
This is another paper on T-cell senescence (previous one here: http://readingrejuvenationresearch.blogspot.com/2010/06/immunosenescence-analysis-and-genetic.html). It focuses on in-vitro studies, saying they are clinically important since that is how immune therapies will likely work best (eg training T-cells on tumor cells outside the body and then reinserting them) to work around the low immune responses of old people. I think their main area of investigation is trying to optimise the conditions under which T-cells replicate the longest.
It says the average number of population doublings (PD) of a T-cell in vitro before it becomes senescent, when externally stimulated, is 17, but 33 for cells that manage to get "established" (ie they get to a million cells). Seems like a very arbitrary cutoff but it better matches the numbers in the previous paper (25-40). The longest living ones reach 80 PDs on average and their record is around 170. They don't know why the large variability exists. The age of the person they were taking from doesn't seem to be one of the important variables. Longevity of CD34+ stem cells differentiated in vitro is no different to that of mature CD3+ cells.
They then switch to the link between telomeres and senescence. Fibroblast telomere length is directly proportional to replicative capacity. They say that this might apply to lymphocytes since the telomere lengths of human blood cells ex vivo are related to donor age, and the rate of telomere shortening with each doubling is about the same as for fibroblasts (120 bp per cell doubling). To me this would contradict what they said before that the replicative longevity was not related to the age of the donor, unless they mean blood cells other than T-cells.
In experiments by other people (Weng, Levine, June, et al) they found that CD4+ memory cells have shorter telomeres than naive cells, and that the difference is independent of the age of the donor. Telomere length decreases during autocrine replication of both of these and naive cells have higher replicative longevity than memory cells. The authors of this paper say this might not give the same results if externally stimulated replication was being used, since this can go on for way longer than the capacity for the cells to secrete interleukin-2, which triggers replication under autocrine replication, and that it doesn't necessarily follow that telomere length is the determining cause of senescence. Telomerase activity is upregulated in T cells when stimulated with CD3 and CD28 simultaneously but this might not happen optimally under various experimental setups, and might not happen optimally in-vivo due to decreased expression of CD28 with age. This, they say, might be the driving mechanism to senescence.
From small experiments they ran on oldish (<35 PD) and older (>43 PD) CD4+ cells, they noticed an upregulation of three mitotic inhibitors (p16-INK4alpha, p21-WAF, and p27-kip1) which suggest that upregulation of mitotic inhibitors might be an alternative hypothesis as the cause of senescence.
)))
Abstract follows:
Interestingness: 3
Paper by Graham Pawelec in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.
(((
This is another paper on T-cell senescence (previous one here: http://readingrejuvenationresearch.blogspot.com/2010/06/immunosenescence-analysis-and-genetic.html). It focuses on in-vitro studies, saying they are clinically important since that is how immune therapies will likely work best (eg training T-cells on tumor cells outside the body and then reinserting them) to work around the low immune responses of old people. I think their main area of investigation is trying to optimise the conditions under which T-cells replicate the longest.
It says the average number of population doublings (PD) of a T-cell in vitro before it becomes senescent, when externally stimulated, is 17, but 33 for cells that manage to get "established" (ie they get to a million cells). Seems like a very arbitrary cutoff but it better matches the numbers in the previous paper (25-40). The longest living ones reach 80 PDs on average and their record is around 170. They don't know why the large variability exists. The age of the person they were taking from doesn't seem to be one of the important variables. Longevity of CD34+ stem cells differentiated in vitro is no different to that of mature CD3+ cells.
They then switch to the link between telomeres and senescence. Fibroblast telomere length is directly proportional to replicative capacity. They say that this might apply to lymphocytes since the telomere lengths of human blood cells ex vivo are related to donor age, and the rate of telomere shortening with each doubling is about the same as for fibroblasts (120 bp per cell doubling). To me this would contradict what they said before that the replicative longevity was not related to the age of the donor, unless they mean blood cells other than T-cells.
In experiments by other people (Weng, Levine, June, et al) they found that CD4+ memory cells have shorter telomeres than naive cells, and that the difference is independent of the age of the donor. Telomere length decreases during autocrine replication of both of these and naive cells have higher replicative longevity than memory cells. The authors of this paper say this might not give the same results if externally stimulated replication was being used, since this can go on for way longer than the capacity for the cells to secrete interleukin-2, which triggers replication under autocrine replication, and that it doesn't necessarily follow that telomere length is the determining cause of senescence. Telomerase activity is upregulated in T cells when stimulated with CD3 and CD28 simultaneously but this might not happen optimally under various experimental setups, and might not happen optimally in-vivo due to decreased expression of CD28 with age. This, they say, might be the driving mechanism to senescence.
From small experiments they ran on oldish (<35 PD) and older (>43 PD) CD4+ cells, they noticed an upregulation of three mitotic inhibitors (p16-INK4alpha, p21-WAF, and p27-kip1) which suggest that upregulation of mitotic inhibitors might be an alternative hypothesis as the cause of senescence.
)))
Abstract follows:
Replicative senescence may compromise T cell-dependent immune responses to intermittent or chronic antigenic stimulation. While the impact of senescence in vivo remains hard to ascertain, clonal cultures of T cells in vitro provide models for longitudinal studies of aging in well-defined populations. Functional and phenotypic studies as well as investigations into average and maximal longevity of T cells can be performed conveniently with these cloned cells (the former in fact only with cloned cells). Many of the age-associated alterations observed during culture in vitro have also been noted ex vivo in T cells from the elderly.
Moreover, under circumstances where large numbers of antigen- and function-specific T cells may be required, for example for adoptive immunotherapy, the in vitro longevity of the cells may be critically important to successful outcome. These considerations are discussed in the following commentary in the context of immunotherapy of cancer.
Sunday, October 17, 2010
The Telomere Shortening Signal May Be Explained by a Fountain Mechanism Modulating the Expression of Eukaryotic Genes
Summary: Speculation on the mechanism involved in telomere-shortening bringing about cell senescence
Interestingness: 4
Paper by AM Olovnikov in the Journal of Anti-Aging Medicine, Volume 2, Issue 1, Spring 1999.
(((
This dude hypothesised that telomere shortening was the trigger for cell senescence and the existence of telomerase back in the 70s. He now gets to publish whatever he wants about telomeres like the hypothesis in this paper. By the present time (2010) biologists probably know if the theory has any merit but I don't, so to me it's still interesting. The idea is more about basic cell biology than about aging. Its only link with aging is that it explains cell senescence via telomere shortening.
The theory tries to explain how it is that telomere shortening causes senescence. It proposes that some bits of RNA bind to and open Ca2+ and Zn2+ channels on the nuclear membrane, and that the influxes of these ions into the nucleus are critical to the transcription of some/most genes. When telomeres shorten, they would physically pull genes near the telomeres out of the areas where these ion influxes happen and therefore they would stop being transcribed, or at least their transcription patterns would be significantly altered. From what I can tell, the specific bits of RNA, which he calls fountain RNAs (fRNAs), and the importance of the ions to transcription are both speculation.
He says that the location and orientation of the chromosomes between G1 and S phase are nonrandom. The telomeres attach to the nuclear membrane, and the bits of attachment are a reinforced section of the membrane that lack the ion channels in question. As the genes near the telomeres get pulled in closer to the membrane, they would also miss out on the ions.
The fRNAs would be composed of two sections, one that would bind to a section of the genome close to the genes that are going to be induced by the ions, and the other section to the ion channels. The sections of the genome to which the fRNA binds to are called converters. The section of the fRNAs that bind to them would vary depending on which section of the genome the fRNA is meant to stimulate. The other section of the fRNA that binds to the channels, in order to open them, would be constant per channel type, Ca2+ and Zn2+ (although the choice of these two doesn't seem central to the theory, and Mg2+ is listed as another option), but the fRNA wouldn't be able to bind to the channel without having first bound to its converter. The activation of the bits of DNA that code for the fRNAs themselves, called modulators, could themselves be controlled by the ionic fluxes so all sorts of feedback loops and modulation of gene expression would exist.
I had problems distinguishing which bits of the paper were speculation and which parts are presented as evidence. From what I can tell, the following are some of the snippets given as supporting evidence for the theory:
)))
Abstract follows:
Interestingness: 4
Paper by AM Olovnikov in the Journal of Anti-Aging Medicine, Volume 2, Issue 1, Spring 1999.
(((
This dude hypothesised that telomere shortening was the trigger for cell senescence and the existence of telomerase back in the 70s. He now gets to publish whatever he wants about telomeres like the hypothesis in this paper. By the present time (2010) biologists probably know if the theory has any merit but I don't, so to me it's still interesting. The idea is more about basic cell biology than about aging. Its only link with aging is that it explains cell senescence via telomere shortening.
The theory tries to explain how it is that telomere shortening causes senescence. It proposes that some bits of RNA bind to and open Ca2+ and Zn2+ channels on the nuclear membrane, and that the influxes of these ions into the nucleus are critical to the transcription of some/most genes. When telomeres shorten, they would physically pull genes near the telomeres out of the areas where these ion influxes happen and therefore they would stop being transcribed, or at least their transcription patterns would be significantly altered. From what I can tell, the specific bits of RNA, which he calls fountain RNAs (fRNAs), and the importance of the ions to transcription are both speculation.
He says that the location and orientation of the chromosomes between G1 and S phase are nonrandom. The telomeres attach to the nuclear membrane, and the bits of attachment are a reinforced section of the membrane that lack the ion channels in question. As the genes near the telomeres get pulled in closer to the membrane, they would also miss out on the ions.
The fRNAs would be composed of two sections, one that would bind to a section of the genome close to the genes that are going to be induced by the ions, and the other section to the ion channels. The sections of the genome to which the fRNA binds to are called converters. The section of the fRNAs that bind to them would vary depending on which section of the genome the fRNA is meant to stimulate. The other section of the fRNA that binds to the channels, in order to open them, would be constant per channel type, Ca2+ and Zn2+ (although the choice of these two doesn't seem central to the theory, and Mg2+ is listed as another option), but the fRNA wouldn't be able to bind to the channel without having first bound to its converter. The activation of the bits of DNA that code for the fRNAs themselves, called modulators, could themselves be controlled by the ionic fluxes so all sorts of feedback loops and modulation of gene expression would exist.
I had problems distinguishing which bits of the paper were speculation and which parts are presented as evidence. From what I can tell, the following are some of the snippets given as supporting evidence for the theory:
- Ca2+ can increase both transcriptional activity and mRNA stability, increases promoters and RNA levels
- There are Ca2+ releasing channels in the inner nuclear membrane and the nuclear envelope has a store of Ca2+
- Zn2+ involvement in zinc fingers, and their involvement in everything DNA
- Explains the long spacers between genes as spacers decoupling the ionic activation between the genes
)))
Abstract follows:
We propose a possible mechanism for the telomere shortening signal. The suggested solution of this as yet unsolved enigma—how cell senescence is causally linked to telomere short-ening—is based on a "fountain theory" of modulation of eukaryotic gene expression, in which gene expression is modulated by ionic channels of the inner nuclear membrane. These Ca2+ and Zn2+ channels are opened transiently through the action of a special small nuclear RNA (the fountain RNA or fRNA) on the ionic channels as conformational changes of the fRNA and channel-forming protein occur. Specific Ca2+ and Zn2+ ion channels allow these ions to pass from the perinuclear lumen to the nucleoplasmic gene surroundings. The resultant change of ionic concentration in close vicinity to certain genes, in turn, will alter some in- properties (e.g., mRNA stability, transcript maturation, chromatin configuration, transcriptional activity, and so forth).
Such fRNA-dependent ionic "fountains," may serve as a major mechanism regulating quantitative gene (phenotypic) expression in eukaryotes. We suggest that among metal-activated transcription factors, zinc-finger nuclear proteins evolved, and they are used in the nucleus as an alternative, noncalcium, path of gene-activity modulation, by means of fRNA-dependent channels, increasing the versatility of a fountain system.
We further propose that telomeres are anchored—in a compacted state—to special reinforcing shields, which are parts of the nuclear lamina along the inner nuclear membrane. This may be particularly true between Gl and S phases of the cell cycle, when chromosomes have nonrandom allocation within a nuclear space and telomeres are compacted and serve as "spacers" between the subtelomeric chromosome and the inner nuclear membrane. Each reinforcing shield would cover a portion of the inner nuclear membrane and, in doing so, prohibit the action of fRNA-dependent ion channels, causing an ionic "dead zone" in the nuclear membrane located immediately beneath the shield. When telomeres are long (e.g., in young cells), subtelomeric genes are located at a relatively greater distance from such dead zones; when telomeres shorten and reach the critical threshold, subtelomeric genes become closer to the dead zone and are deprived of contact with active ion channels. Shortening of the telomere—and therefore of the distance of subtelomeric genes from the dead zone—alters subtelomeric gene expression, decreases the functional capabilities of the cell, and results in cell senescence.
In some species, such subtelomeric genes may encode the fRNAs themselves, in addition to structural genes. If modulator genes—coding for fRNAs—require the ion fountains for optimal expression, then other structural genes (in turn modulated by such genes) will inevitably show senescence-associated gene expression as the telomere shortens. Such an alteration of gene expression, and the consequent dysfunction in cellular homeostasis, are typical of senescing cells.
Sunday, June 20, 2010
Immunosenescence: Analysis and Genetic Modulation of Replicative Senescence in T Cells
Summary: T-cell senescence might be an important part of aging.
Interestingness: 4
Paper by Rita B Effros and Hector F Valenzuela in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.
(((These people want to try out upregulating telomerase in old T-cells)))
A major part of the function of T- and B-lymphocytes is based on replication. When differentiating from hematopoietic stem cells, the molecules or particles which the future mature lymphocytes are sensitive to (aka antigens) are encoded by a few sequences of DNA which are combined in random fashion. This makes the system potentially sensitive to hundreds of millions of different antigens. When an antigen is bound by a lymphocyte, the lymphocyte starts replicating, making identical clones (ie their receptor which sensed the antigen is not modified). When the antigen is no longer found in the environment, most of the lymphocytes disappear, but a few memory lymphocytes with the particular receptor remain so that the system can be revved up faster the next time that specific antigen is in the system.
Senescent T-cells can be generated in vitro by repeatedly exposing them to interleukin-2 (IL-2), a T-cell specific growth factor. After about 25-40 replications, they become senescent (ie they stop replicating). Fibroblasts (connective tissue cells) also become senescent after about 21 replications.
The receptor CD28 is not expressed in 95% of CD8+ senescent T-cells, and in all CD4+ senescent T-cells. Without CD28 costimulation, antigen binding doesn't lead to cell replication. CD28 signal transduction upregulates IL-2. It is also hypothesised to upregulate telomerase activity. Telomerase is very active in lymphocytes under certain conditions: in developing T-cells in the thymus and in lymphoid organs, when stimulated with mitogens (particles that upregulate replication), or by combination of antibodies to CD3 and CD28. When CD28 binding is inhibited, telomerase remains inactive even if there is strong stimulation of its T-cell antigen receptor (TCR). Even though telomerase is sometimes active in T-cells, senescent T-cells have short telomeres typical of other senescent cells. When split into CD28+ and CD28- T-cells, CD28- cells have shorter telomeres and lower replicative capacity when stimulated.
In vivo, CD28- T-cells are 1% fraction of neonates' total T-cells, 30% of (average) 78 year olds, 40% of people over 100, and 50% of HIV patients. Telomere lengths also shorten in peripheral blood lymphocytes as age increases. This loss of CD28 and shortening of telomeres is more pronounced in CD8+ cells, which specialise in anti-viral and anti-tumor activity, than in CD4+ cells (((doesn't this contradict the earlier numbers of 95% in CD8 and all in CD4?))). This could be due to infections by viruses that do not disappear (eg Epstein-Barr, varicella) or by repeated infections (eg influenza).
As people age, memory T-cells become a larger fraction of all T-cells. Senescence is also more common among memory cells. Non-senescent T-cells in old people respond to activation as strongly as those in young people.
During normal immune system activity, once the antigen dissapears from the system, most T-cells die by apoptosis. Senescent cells respond to apoptotic signals much less strongly, especially among CD8+ cells. These leftovers memory T-cells could be crowding out the production of new more useful T-cells. In calorie restricted mice, apoptotic response is maintained at youthful levels.
Abstract follows:
Interestingness: 4
Paper by Rita B Effros and Hector F Valenzuela in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.
(((These people want to try out upregulating telomerase in old T-cells)))
A major part of the function of T- and B-lymphocytes is based on replication. When differentiating from hematopoietic stem cells, the molecules or particles which the future mature lymphocytes are sensitive to (aka antigens) are encoded by a few sequences of DNA which are combined in random fashion. This makes the system potentially sensitive to hundreds of millions of different antigens. When an antigen is bound by a lymphocyte, the lymphocyte starts replicating, making identical clones (ie their receptor which sensed the antigen is not modified). When the antigen is no longer found in the environment, most of the lymphocytes disappear, but a few memory lymphocytes with the particular receptor remain so that the system can be revved up faster the next time that specific antigen is in the system.
Senescent T-cells can be generated in vitro by repeatedly exposing them to interleukin-2 (IL-2), a T-cell specific growth factor. After about 25-40 replications, they become senescent (ie they stop replicating). Fibroblasts (connective tissue cells) also become senescent after about 21 replications.
The receptor CD28 is not expressed in 95% of CD8+ senescent T-cells, and in all CD4+ senescent T-cells. Without CD28 costimulation, antigen binding doesn't lead to cell replication. CD28 signal transduction upregulates IL-2. It is also hypothesised to upregulate telomerase activity. Telomerase is very active in lymphocytes under certain conditions: in developing T-cells in the thymus and in lymphoid organs, when stimulated with mitogens (particles that upregulate replication), or by combination of antibodies to CD3 and CD28. When CD28 binding is inhibited, telomerase remains inactive even if there is strong stimulation of its T-cell antigen receptor (TCR). Even though telomerase is sometimes active in T-cells, senescent T-cells have short telomeres typical of other senescent cells. When split into CD28+ and CD28- T-cells, CD28- cells have shorter telomeres and lower replicative capacity when stimulated.
In vivo, CD28- T-cells are 1% fraction of neonates' total T-cells, 30% of (average) 78 year olds, 40% of people over 100, and 50% of HIV patients. Telomere lengths also shorten in peripheral blood lymphocytes as age increases. This loss of CD28 and shortening of telomeres is more pronounced in CD8+ cells, which specialise in anti-viral and anti-tumor activity, than in CD4+ cells (((doesn't this contradict the earlier numbers of 95% in CD8 and all in CD4?))). This could be due to infections by viruses that do not disappear (eg Epstein-Barr, varicella) or by repeated infections (eg influenza).
As people age, memory T-cells become a larger fraction of all T-cells. Senescence is also more common among memory cells. Non-senescent T-cells in old people respond to activation as strongly as those in young people.
During normal immune system activity, once the antigen dissapears from the system, most T-cells die by apoptosis. Senescent cells respond to apoptotic signals much less strongly, especially among CD8+ cells. These leftovers memory T-cells could be crowding out the production of new more useful T-cells. In calorie restricted mice, apoptotic response is maintained at youthful levels.
Abstract follows:
Immunosenescence, which constitutes one of the most dramatic physiologic changes associated with aging, may account for the increased susceptibility to infections and the high incidence of cancer in the elderly. A novel facet of T-cell biology has been recently identified that may exert a considerable impact on immune control over infections and cancer during aging. Cell culture studies have shown that after repeated rounds of antigen-driven proliferation, T lymphocytes eventually reach replicative senescence, an irreversible nonproliferative state associated with the loss of expression of a critical T-cell signaling molecule. Identification of this unique, cell-specific marker of senescence has facilitated the documentation and analysis of replicative senescence within the immune system in vivo during aging. This article summarizes the features of T-cell replicative senescence and highlights several genetic strategies that may reverse the process. The ability to manipulate T-cell replicative senescence may ultimately provide a fresh therapeutic approach to extend the years of immunologie "coverage" in the elderly.
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