Rest of volume 3, Issue 2

The rest of issue 2 of 2000 consists of:

A summary of the Templeton conference "Extended Life - Eternal Life" by Michael Fossel. About ethics.

A review of the book "Time of Our Lives: The Science of Human Aging". Book by Tom Kirkwood, review by Robert Arking. Positive review, popular access book.

A review of a paper by Junji Yodoi and Lester Packer, "Redox Regulation in Eukaryotic Cells Based on Thio-Redoxin Enzymes". Interesting bit about mice with upregulated thioredoxyn ("against UV in the bone marrow" it says, no idea what that means in this context) gene having an increased lifespan.

Endocrinology of Benign and Malignant Prostate Disease in Aging

Summary: Prostate cancers are out to get us, and too many hypothesis on why they grow.

Interestingness: 3

Paper by Marco Marcelli, TC Shao and Glenn R Cunningham in the Journal of Anti-Aging Medicine, Volume 3, Issue 2, June 2000.

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This paper is about the relationship between androgens, testosterone (T) and dihydrotestosterone(DHT), and estrogens, and prostate cancer (CaP in the text for some reason, but I'll go with the more obvious PC) and benign prostate hyperplasia (BPH), but the bits that interested me were the general stats and information about PC and BPH. It is also one of those that is a summary itself so there's too much information and I end up paying attention to none of it.

Check these numbers out, mostly related to USA population, male only:

• 28.7% of new, nonskin cancers
• 12.7% of cancer-related deaths
• BPH in 10% of 35 year olds, >80% of 80 year olds.

Latent PCs found in

• 15-20% of 40-50 year olds (found in autopsies, deaths from other reasons)
• >50% of 60-70 year olds.

The latent PC numbers seem especially scary for me. They seem to indicate that if we do extend lifespan, these will become active problems, not just latent.

The study focuses quite a bit on cross-ethnic variation of PC and BPH rates, and correlations or lack thereof with androgen levels. It then runs through the non-exclusive hypothesis for the cause/s of BPH and PC. For BPH: increased androgen concentration, something about estrogen, dysregulation of growth factors, and an increased in the number of stem cells. For PC: mutation in SRD4A2, androgen receptor (AR) gene codon repeats, and insulin-like growth factor 1 (IGF-1). I didn't pay much attention to the details of the hyopthesis.

Treatment/preventions: 5alpha-reductase inhibitors (5alpha-reductase converts T to DHT), like finasteride, which supposedly work well in the prevention of BPH, but don't do much once BPH is severe (well, 20-30% reduction in volume). For PC, castration, I assume chemical, induces remission on 80% of PC patients, but it mostly lasts 12-18 months, after which the PC recovers and 70% of the patients die.

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Leptin Resistance with Age-Related Obesity

Summary: Explains the link between leptin, neuropeptide Y (NPY) and obesity in a rat model of age-related obesity they like

Interestingness: 1

Paper by Philip J Scarpace and Nihal Tümer in the Journal of Anti-Aging Medicine, Volume 3, Issue 2, June 2000.

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They found a type of rat, F-344xBn, that gains weight in a similar manner to humans, slowly building up until 60 years of age/24 months for human/rat, and then slowly going down.

In young rats, higher leptin led to lower NPY. "NPY stimulates feeding and decreases energy expenditure". Fasting lowers leptin levels. Leptin is produced by white adipose tissue (not sure if only there). In young rats, there's a nice inverse relation between NPY and leptin. The relation isn't clear in old rats, and the inhibition of NPY by leptin also becomes clear. They track the relation to some other proteins and brown adipose tissue, but I don't care enough so I'd probably misrepresent the content.

They think the same thing could be true in humans. I remember something about leptin acting differently in rats (or was it mice) and humans. Maybe not in these rats.
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Abstract follows:

Leptin, synthesized by white adipose tissue, interacts with the appetite and satiety centers to regulate body weight, and this hormone contributes to the regulation of both food intake and energy expenditure. Serum leptin is elevated in most obese humans, and that obesity persists in spite of the elevated leptin, suggesting leptin resistance. The F-344xBn rat strain, similar to humans, demonstrates a steady increase in body fat and serum leptin into early senescence. Thus, these aged rats become obese in spite of the elevated leptin, suggesting the relationship between leptin, adiposity, and food intake is altered with age. Leptin modulates a number of neuropeptides in the hypothalamus, including neuropeptide Y (NPY). NPY both stimulates feeding and suppresses thermogenesis in brown adipose tissue. Following leptin infusion, the decrease in food intake and the increase in energy expenditure were blunted in the aged rats. Moreover, leptin decreased NPY mRNA in young but not senescent rats, suggesting that leptin signal transduction may be impaired. Leptin receptor signal transduction involves phosphorylation of cytosolic signal transducer and activator of transcription (STAT) proteins, specifically phosphorylation of STAT3 (P-STAT3). Leptin-induced P-STAT3 levels were unchanged with age, but the dose of leptin required for half maximal stimulation was 5-fold greater in the older rats, suggesting that sensitivity for leptin signal transduction is diminished with age. In summary, aged rats demonstrate a reduced responsiveness to leptin, and the mechanism may involve impaired suppression of hypothalamic NPY mRNA that may be a consequence of impaired leptin signal transduction. This leptin resistance may be due to either the elevated obesity and serum leptin with age or due to age itself or both.

Contemporary Clinical Research on Menopause

Summary: More studies needed on menopause

Interestingness: 1

Paper by Robert W Rebar in the Journal of Anti-Aging Medicine, Volume 3, Issue 2, June 2000.

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I think this is meant to be a review paper but it doesn't have much content. The author wants some interventional studies done. There doesn't seem to be any reliable predictive markers of when menopause will happen. Hot flashes happen to 85% of women during the perimenopausal and early menopausal periods. Estrogen sometimes cures hot flashes. Author doesn't like studies that combine women without ovaries with ones that do, and the same about women with premature ovarian failure. That's it.
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Abstract follows:

To the present time, knowledge about menopause has accumulated largely because of observational and epidemiological studies in postmenopausal women. The challenge for the years ahead is to utilize the information learned from several large epidemiological studies, including the Postmenopausal Estrogen-Progestin Intervention (PEPI) trial, the Women's Health Initiative (WHI), and the Study of Women's Health across the Nation (SWAN), to develop testable hypotheses. Studies of pharmacological agents have also provided information that may be of use in this regard. Some women with so-called premature ovarian failure may form another appropriate experimental group. Appropriate questions for future study are abundant. Why do some women develop vasomotor instability, whereas others never complain of any associated symptoms? Can we predict which women will develop osteoporosis and which will not? Which changes occurring after menopause are related to the cessation of ovarian function and which changes are related to aging? Investigation of these and other such questions will require a return to clinical research that is not population based. This presentation will review some of the advances that have been made by clinical investigation and suggest approaches and questions for the years ahead.

Progress in Erectile Dysfunction and Hormone Function

Summary: If your dick don't work try Viagra

Interestingness: 1

Paper by Pejman Cohan and Stanley G Korenman in the Journal of Anti-Aging Medicine, Volume 3, Issue 2, June 2000.

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Lots of overlap between this paper and the previous two. It describes the mechanism of how an erection comes to be and all the stages at which it can stop working, the non-effectiveness of testosterone in solving the issue, even though it helps with libido (something that the previous paper had some doubts over), and then lists possible solutions with Viagra at the top of the list, supposedly working 50-70% of the time.

Some interesting random numbers from the rest:

• Testosterone drops 110 ng/dL every decade.
• 15% of people over 80 had normal levels of testosterone in a study of 300.
• In the Massachusetts Male Aging Study, which google tells me was on 1290 men, a quarter of the 40-70 year olds had a moderate degree of erectile dysfunction (ED). Not sure what a moderate amount is though

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Abstract follows:

The concept of "andropause" has recently gained popularity as increasing evidence suggests that aging in men is accompanied by a progressive decline in serum testosterone levels. The pathophysiologic mechanism responsible for this decline is not fully understood. However, perturbations at every level of the hypothalamic-pituitary-gonadal system have been demonstrated. Age is also a strong risk factor for erectile dysfunction (ED). Although it is tempting to conclude that a causal relationship exists between declining androgen levels and ED, our current understanding of the erectile process and the failure of testosterone supplementation to restore erectile function in older men suggest that these processes are independent. Furthermore, the recent availability of effective oral therapies for ED argues against the indiscriminate administration of androgens to elderly men with ED. However, the beneficial effects of testosterone on libido, mood, bone density, and body fat composition may justify its use on an individual patient basis.

Endocrine Determinants of Successful Aging in the Male

Summary: A whole bunch of hormone levels go down when men get old

Interestingness: 3

Paper by Annewieke W van den Beld and Steven WJ Lamberts in the Journal of Anti-Aging Medicine, Volume 3, Issue 2, June 2000.

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This is another paper that reads like a review paper, even though they keep referring to their study of 400 73-94 year old men in the Netherlands. Most of what's quoted is about other studies. When they talk about their own study, I'll note it, and I'll mainly focus on their results, not the survey. Their study mostly lacks graphs and numbers, so I'll stick to what they describe it as (increase, decrease, etc).

They "confirm" other studies that say that muscle strength is the major feature that determines whether an old man remains functionally independent.

Mean serum total testosterone (T) in males goes down by about 30% between being 25 and 75. Mean serum free T goes down by 50%. The difference is explained by an increase in sex-hormone-binding globulin (SHBG). In their study they found a correlation between free T and muscle strength, but none between T and life satisfaction.

In their study they see luteinising hormone (LH), which triggers release of T by the testicles, going up with age, and it being inversely correlated with T concentrations. Other studies show mixed results for this relation.

Drop in estradiol (E2) and estrone (E1) with age. In their study, strong correlation between E2 and bone density, and E2 and life satisfaction.

Drop in dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS) with age. DHEAS level at 85 is one fifth of level at 30. DHEAS levels in adults > 10 times higher than cortisol (!). In their study, no relation between DHEAS and muscle strength, and relation between DHEAS and bone density disappears when adjusting for T and E1,E2 levels.

And again growth hormone (GH) secretion drops with age, insulin-like growth factor 1 (IGF-1) drops with age, IGF-binding protein 3 (IGFBP-3) drops with age, but IGFBP-2 and IGFBP-1 increase with age. Their study concurs. Also in their study, they didn't see relation between IGF-1 and physical functional status, but did see a strong inverse relation between IGFBP-2 and muscle strength, and they like IGFBP-2 as an indicator of overall level of physical functional status.
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Abstract follows:

Frailty is characterized by generalized weakness, impaired mobility and balance, and poor endurance. Loss of muscle strength is an important factor in the process of frailty, and is the limiting factor for an individual's chances of living an independent life until death. In men, several hormonal systems show a decline in activity during aging. Serum bioavailable testosterone (T) and estradiol (E2), dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), and growth hormone (GH) and insulin-like growth factor (IGF)-I concentrations all decrease during aging in men. Physical changes during aging have been considered physiological, but there is evidence that some of these changes are related to this decline in hormonal activity. Studies on hormone administration in the elderly appear to be promising. However, until now, hormone replacement is not yet proven to beneficial and safe.