Prevalence and Risk Factors of Cognitive Deficits and Dementia in Relation to Socioeconomic Class in an Elderly Population of India

Summary: Study of dementia and pre-dementia in India, how it relates to behavioural and economic factors, difficulties of doing such research, all with expected results

Interestingness: 1

Paper by RB Singh, R Singh Rao, AS Thakur, S Srivastav, MA Niaz and SN Shinde in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.


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The abstract is a perfect summary of the results. The paper mainly describes the process of the survey and how it had to be changed to make it work in India. The results are pretty much what I expected, except for the alcohol intake correlation.

It comes with an appendix with the questions in the survey. That bit is fun, even though the results are a little bit troubling.
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Abstract follows:

We attempted to find the association between age-related cognitive deficits or dementia and socioeconomic class or other risk factors, using a cross-sectional random survey of 595 elderly subjects ages 50-84 years in an urban population of Moradabad, India. The prevalence of cognitive deficit was 18.6% and was significantly higher in men than women (22.3% vs 14.6%; P < 0.05). There was a greater prevalence of cognitive deficits in lower socioeconomic classes. The prevalence of cognitive deficit, including dementia, has become a public health problem in India and is significantly associated with lower socioeconomic class, higher age, smoking, malnutrition, and alcohol intake in men.

Estrogen and Brain Aging

Summary: Description of mostly suggestive data about the effects and importance of estrogen on aging in the brain

Interestingness: 1

Paper by Mahendra K Thakur in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.


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The most interesting part of the paper is a mention of a result in some other paper that women receiving estrogen replacement therapy (ERT) are 40% less likely to have Alzheimer's disease (AD) than women not receiving ERT.

The rest is a description of the changes in neurotransmitter and receptor densities in the brain as it ages, how estrogen might affect those neurons that produce and receive those neurotransmitters, mainly going by rat studies, results of women's mental scores going down when taking medication that suppresses estrogen production, and how those scores are rescued when taking ERT. I'm not good at absorbing the neurotransmitter information, so I glazed over a lot of it. Nerve growth factor seemed to be mentioned a lot.

There was also mention of estrogen as an antioxidant and its relation to AD. My biases prevailed and I discounted all of it before it even hit my long term memory.
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Abstract follows:

Recent research findings have made it clear that the female sex-steroid hormone estrogen has several functions other than regulation of sexual and reproductive behavior. In addition to this hormone's well-known influence on bone and the heart, this hormone exerts a wide variety of effects on the brain, including both development and function. The current interest in aging of the brain derives, in part, from the enormous and global increase in the proportion of elderly people. Old age is associated with several health problems including a general decline in mental function, especially in dementia, and specifically Alzheimer's dementia (AD). To focus on this issue, it is essential to understand the changes taking place in the aging brain and the role that estrogen plays in this process. This article reviews the data on the involvement of estrogen in the aging brain and discusses the potential consequences of estrogen replacement therapy.
Free first page

Is There a Reproductive Cost for Human Longevity? and Human Longevity and Reproductive Success: Response to Gavrilov and Gavrilova

Summary: Critique and response of a study of an implicit tradeoff between number of offspring and mortality.

Interestingness: 1

Paper by Leonid A Gavrilov and Natalia S Gavrilova in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.
Response by Rudi GJ Westendorp and Thomas BL Kirkwood in the same issue.

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This is a critic of a paper that appeared in Nature about a trade off between number of offspring and longevity among the Brittish aristocracy going back to the year 740. Reasonable sounding critique, and reasonable sounding response. The abstract below is a good summary of the critique. The reply shows that adjusting for each of the items in the critique doesn't change the resultant mortality increase associated with having 2 or more children (1.15), and that they get different results from other studies because they restricted themselves to a homogenous group.
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Abstract of first paper follows (second one lacked an abstract):

This is a critical review of the recent claims by Westendorp and Kirkwood that human longevity is achieved at the cost of reproductive success. The criticism could be summarized in four statements. (1) Declaring that long-lived women have less progeny and older age at first childbirth, the authors failed to adjust the data for the age at marriage—the most important explanatory variable both for the number of children and for the age at first childbirth; (2) they also overlooked another important confounding variable—the husband's fertility; (3) the authors used the data that are inappropriate for fertility studies—extremely ancient and incomplete genealogies with many underreported records for daughters that led to incorrect estimates for the number of progeny and for the age at childbirth; and (4) the authors presented their study as completely new for humans and did not quote the opposite results from the earlier study by Le Bourg et al. where no trade-off between human longevity and fertility was observed. They also ignored findings of Bideau and of Knodel that the most fertile women live longer than the remainder or at least not shorter contrary to the author's claims. Thus, the conclusions of Westendorp and Kirkwood are inconsistent with the existing knowledge and should be reanalyzed using more appropriate methods and data.

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.

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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.
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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.

Rest of Volume 2, Issue 1

The rest of issue 1 of 1999 consists of:

A report on the 51st annual meeting of the gerontology society of America.

A review of:

• Brocklehurst's TextBook of Geriatric Medicine and Gerontology, 5th edition, by R Tallis, H Fillit and JC Brocklehurst (one-stop shop for gerontology, glowing, must have).
• Darwin's Spectre: Evolutionary Biology in the Modern World, by MR Rose (popular science of effects of evolution on aging)
• A Means to an End: The Biological Basis of Aging and Death, by WR Clark (good)
• Age Right: Turn Back the Clock with a Proven Personalized Anti-Aging Program, by K Ullis and G Ptacek (information from sports medicine about aging)
• Aging in the Thrid Millenium, by EL Schneider (a paper in Science)
• Nutrition and longevity: The Johns Hopkins White Papers, by S Margolis and LB Wilder (summary of benefits and risks of various suplements and foods)

Some announcements of research grants by the American Federation of Aging Research.

The usual other sections: web watch, literature watch and calendar.

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.

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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

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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.