A gynecologist – the ultimate “midwife” of fertility, childbirth and womens’ successful midlife – asks: what are the pathogenetic mechanisms common to the increasing fractures, increasing stroke-cardiovascular and malignant disease in the aging?
It goes without saying that we humans are our own worst enemies and the greatest threat to heathy survival of life. But bad choices and diet-lifestyle, Silent Spring, and Oryx and Crake aside:
CANCER – the least common clinically, that kills or cripples below 5%- is perhaps easier to generalize: poisons like smoking, alcohol and asbestos aside, the common cancers of the latter half of life – the sex-hormone-related cancers- generally take decades to reach clinical significance, and involve many mechanisms including genetic, environmental, alcohol, smoking, lack of exercise, dietary and above all, random mutations and progressive dysregulation of aging and the millieu interieur.
It is common cause that in both longterm historical followup clinics (Byrd & Burch; Schleyer-Saunders; Gelfand; Greenblatt Gambrell et al; the Nurses Study); and in the trials- the Womens’ Health Initiative (2002, 2004) and the Oulu trial (Heikkinen 2006), women randomized to appropriate conservative dose oral estrogen-progestin from menopause and followed for up to 10 or more years had virtually one-third reduction in all common major diseases including breast and colon cancer, fractures, cardiovascular and dementing diseases, and in cancer- and all-cause mortality. Men followed for a decade and more from initiation of appropriate parenteral testosterone supplementation have similar striking reduction in prostate cancer and in cancer-and all-cause mortality (Behre & Nieschlag Germany; Carruthers London; Kaufman USA)
CARDIOVASCULAR-STROKE DISEASE: it has been recognised for decades that antioxidants, and the three antihomocysteine vitamins (B6 B9 B12), and the 150year old nitric oxide promoter nitroglycerin NG are major benefit against chronic CVD and it’s symptoms if not during acute myocardial infarction and stroke. NG remains the mainstay of treatment for angina.
In acute myocardial infarction, the timing of intravenous NG seems to be crucial if it is to lessen morbidity and mortality (Jugdut Canada 1988), and similarly oral NG seemed to have no benefit following acute myocardial infarction (Ishikawa Japan 1996) except with heart failure (Fitzgerald 1990); but timeous transdermal NG may give beneficial improvement in cerebral bloodflow after subarachnoid hemorrhage (Reinert Switzerland 2006).
There are apparently no definitive randomized controlled trials on Medline of chronic NG use in patients with chronic angina. But after angioplasty, restenosis angina responds well to NG (42% incidence) compared to placebo (75%; p<0.003). NG lowered the repeat angiography rate from 23% to 4%. (Doucet 2000).
Ignoring fracture incurred as a result of a stroke-induced fall, or visa versa; and ignoring disuse osteoporosis after stroke:
what factors contribute simultaneously to aging osteoporosis and stroke-cardiovascular disease CVD?
A forthcoming paper (Kanawasa ea Japan Oct 2008) “suggests that metformin can induce the differentiation and mineralization of osteoblasts via activation of the AMPK signalling pathway, and that this drug might be beneficial for not only diabetes but also osteoporosis by promoting bone formation”. It is common cause that diabetes is associated with weaker bones and more fractures (Yamamoto 2006).
Metformin (Werner & Bell 1922) is dimethylguanidine- the only synthetic drug (a tagged antihyperglycemic extract of the galega officinalis plant) that has been proven to be a panacea against virtually all major diseases, a heavy-metal chelating, antimicrobial fibrinolytic antineoplastic antihypertensive antioxidant insulin sensitizer (without increasing C peptide) that also reduces lipidemia; and bone resorption (and thus unblocks obesity-related delayed adolescent growth) via promotion of nitric oxide synthase- possibly via AMP(Kim 2007). It is the only designer drug ever that has been proven in a 20 year randomized controlled trial RCT (mean 13.6yrs- the UKPDS, Holman ea 1998) to reduce all major adverse events including cancer and allcause mortality by 36% in diabetics; and reduce new diabetes by about 50% (30 – 70%) in major prevention trials in prediabetics over a mean of about 3 years in the USA, India and Chinese Diabetes Prevention Programs- without a singe major adverse effect. No other designer drug for chronic prevention can claim such multisystemic benefits and lack of adverse effects in sensible tolerable dose.
By contrast, Osdoby ea 1994 reported that the nitric oxide inhibitor “aminoguanidine also caused a loss of bone mineral density – Inhibition of NOS activity in vitro and in vivo resulted in an apparent potentiation of osteoclast activity”. So while aminoguanidine was promoted a decade ago as an antiaging antidiabetic drug against AGES Advanced Glycation Endproducts it has not replaced metformin – despite promises, and thousands of papers about it on Medline dating back to 1950, no clinical trial results have in fact been published on Medline showing aminoguanidine has any significant longterm benefits. The severe toxicity reasons (the ACTION ll trial) for this are detailed by Montagnani 2008.
Nitric oxide is a key vasodilator, neurotransmitter and immunomodulator; it’s therapeutic level is boosted by nitroglycerine; metformin (Kanazawa 2008); human sex hormones and arginine.. Nobel prizewinner Ferid Murad ea 2008 note that “NO-mediated signalling is a recognized component in various physiologic processes (eg, smooth muscle relaxation, inhibition of platelet and leukocyte aggregation, attenuation of vascular smooth muscle cell proliferation, neurotransmission, and immune defence), to name only a few. NO has also been implicated in the pathology of many inflammatory diseases, including arthritis, myocarditis, colitis, nephritis and a large number of pathologic conditions such as amyotrophic lateral sclerosis, cancer, diabetes, and neurodegenerative diseases. Some of these processes (eg, smooth muscle relaxation, platelet aggregation, and neurotransmission) require only a brief production of NO at low nanomolar concentrations and are dependent on the recruitment of cyclic guanosine monophosphate (cGMP)-dependent signalling.” So, as with oxygen, vitamins, minerals, biologicals, foods, alcohol and all therapeutics, balance – the right amount- is everything.
Interestingly, while arginine and appropriate testosterone-estrogen supplements usually boost insulin sensitivity as well as low growth hormone HGH levels and thus anabolism in bone, muscle etc, a nitric oxide promoter eg nitroglycerin in its own right has the same benefit as ERT in preserving good bone mass (Hao ea China 2005). This was already shown in chicks by Osdoby ea 1994, based on a postulate by MacIntyre ea 1991 . – who subsequently demonstrated this in rats (MacIntyre 2003).
Estrogen is a known immunostimulator whereas progesterone and testosterone are known immunomodulators. In vitro, estrogen too may have a dimorphic effect on nitric oxide (Walsh 2003; Shih 2006; Richette 2007). But in postmenopausal women transdermal or oral ERT with or without cyclic progestin for 6 – months increases NO levels (Serin 2001; Kesim 2005).
Pance 2006 notes that “estrogen and progesterone regulate the nitric oxide synthases (NOS) and, in turn, the NO produced has profound consequences on tumor cell homeostasis. On one hand, estrogen increases the activity of endothelial NOS (eNOS or NOSIII), while progesterone activates inducible NOS (iNOS or NOSII) expression. The data presented suggest that the low levels of NO produced by NOSIII mediate the proliferative effect of estrogen. On the other hand, the increase in apoptosis in response to progesterone could implicate the high levels of NO produced by induction of NOSII expression”
Testosterone on the other hand is the well-known crucial erectile stimulator of nitric oxide synthetase (Shabsingh 2004) .
So apart from genetic programming and accumulating levels of environmental toxins, there are at least six possible pathophysiologies common to the preventible aging comorbidities of apoptosis, fattening-diabetes-cancer; osteoporosis-fractures, and CVD-stroke:
*catabolism by gonadopause deficiency without a balancing fall in catabolic cortisol levels;
*nitric oxide depletion;
*increased reactive oxygen species ROS due to depleting endogenous and dietary antioxidants;
*common aging-related deficiency of minerals eg magnesium, zinc,chromium, lithium; vitamins; and human biologicals eg chondroglucosamine, CoQ10, carnitine, ribose, arginine, carnosine, Nacetylcysteine;
*insulin resistance – prediabetes, metabolic syndrome, diabetes; and
*accumulating multiple metal overload eg cadmium, iron, aluminium, mercury, lead, arsenic copper (even zinc and iron) from smoking, food and environmental pollution that can simultaneously promote cancer, neurovascular and osteoporosis problems
Obviously the basket of natural supplements- fish oil, cal-mag zinc boron, the vitamins A ( bcarotene) to K, and the human biologicals proline, CoQ10, arginine, ribose, carnitine and appropriate hormone balance with eg testosterone-estradiol, growth hormone, and galega extract, are trophic in improving anabolism, antioxidation, optimal NO levels and preventing AGES, atheroma and arteriosclerosis as well as collagen and mineral loss from diverse muscle and bone – ie preventing many of the risk factors for both fractures (frailty, weak bones and muscles – skeletal and smooth ie gastrointestinal and heart ) and vascular disease .
Given the common pathogenetic factors of all the common major aging diseases, one should simply add natural arginine glutamine and proline, in addition to the vitamins, minerals, glucosamine-chondroitin, and the other natural insulin sensitizers eg N acetyl cysteine, ribose, carnitine, CoQ10 and galega officinalis, to the natural supplements to combat all aging diseases; and when hypogonadism becomes likely- with chronic illness, or from middle age- add appropriate parenteral balanced physiological-dose testosterone-estradiol- progesterone to restore the average levels of healthy slim youthful adults.
While some of these above may be chelators in their own right, the high prevalence of metal overload may justify routine addition to supplements (within recognized tolerance and safe limits) of extra harmless putative chelators like calcium EDTA, carnitine, bromelain, garlic, malic acid, cysteine, lipoic acid, vitamin C, selenium, thiamine, magnesium, selenium, zinc and bromelain.
The first comment attached below is appropriately from
Professor Frederick Naftolin MD, PhD, FACOG, FRCOG
past Chairman of OB/GYN at McGill and Yale Universities, then Prof of Biology at Yale,
now Professor of Obstetrics and Gynecology
Director, Reproductive Biology Research
Co-director Interdisciplinary program in Menopause Medicine
New York University School of Medicine