Endocrinology of Aging

ABBREVIATED LECTURE NOTES TAKEN AT AN INTERNATIONAL SYMPOSIUM OCTOBER 27, 1999, IN TEMPE, ARIZONA

These are Dr. Cranton’s abbreviated notes from a 2-day symposium in October 1999. The faculty included university and medical school professors from institutions around the world, including Johns Hopkins University, NIH, Mayo, Harvard, UVA, UCLA, UCSF, and many more. Some faculty members came from foreign countries, including England, Italy, Holland, and Austria. This was an excellent conference with an excellent faculty. The information below is condensed from lecture notes and from informal discussions with the faculty.

SYMPTOMS OF AGING REPORTED TO REVERSE WITH HGH REPLACEMENT IN A RECENT MEDICAL SCHOOL STUDY

•> Insulin resistance and loss of glucose tolerance improved
•> Decreasing lipolysis (slower breakdown of fat) improved
•> Increased serum triglycerides and LDL cholesterol improved
•> Loss of heart muscle size (smaller left ventricle) improved
•> Decreased metabolic efficiency and exercise tolerance improved
•> Decreased immune B and T cell lymphocytes improved
•> Progressively impaired immunity improved
•> Thinning and bruisability of skin improved
•> Slower hair growth improved
•> Slower healing improved
•> Impaired sleep improved
•> Impaired mood improved
•> Diminished sense of well being improved
•> Impaired body image improved

Ongoing studies continue to confirm benefits as first reported in the Rudman HGH study, published in the New England Journal of Medicine almost a decade ago.

RESISTANCE DEVELOPS TO ALL GROWTH HORMONE SECRETAGOGUES

Resistance gradually develops to all growth hormone secretogogues taken by mouth or injection, even to pure hypothalamic recombinant growth hormone releasing hormone (rGHRH) and growth hormone releasing peptides (GHRP). Resistance occurs gradually after the first few months of use. Even the most effective secretagogues have limited long term benefit.

Secretagogues that stimulate HGH release also stimulate ACTH and increase cortisone levels produced by the adrenal glands, which may increase to undesirable levels with aging anyway. Secretogogues increase abnormal high levels of cortisone, while corticosteroids block benefit from HGH.

Oral secretagogues have only minor benefit and it is common for tolerance to those agents to develop with time (so-called tachyphylaxsis). Merck Pharmaceutical Company discontinued research on one such secretagogue, a peptide mimic called MK-677, partially for that reason.

Cell resistance to peptide hormones occurs with aging, especially insulin

With age, cell receptors lose sensitivity to the action of HGH, insulin, IGF-1, leptin, thyroid, and many other (perhaps all) peptide hormones. This varies from person to person.

Elevated blood insulin levels commonly occur with aging and are one cause of decreasing HGH secretion—insulin has a negative feedback effect on HGH release.

Aerobic exercise acts to partially reverse and slow age-related loss of cell response to peptide hormones. That benefit decreases with age.

Low glycemic index carbohydrates with fewer carbohydrates and simple sugars (requiring less insulin, as used in the Barry Sears’ "Zone" diet) can also improve tissue responsiveness to insulin. This also improves cellular responsiveness to HGH.

Tissue responsiveness to insulin and many other hormones decreases progressively throughout life, beginning at age 17, although there exists considerable individual variability.

Glucose (carbohydrate) tolerance decreases predictably with age from loss of tissue sensitivity to insulin. Secretion of insulin by pancreatic beta cells increases to compensate. Blood levels of insulin thus increase with age and increasing insulin is partially responsible for problems of aging. The end stage of this process is type II, adult-onset, non-insulin-dependent diabetes. If the pancreas becomes exhausted by excess production of insulin, insulin by injection may become necessary late in the disease. Gradual insulin resistance with increased production and elevated blood insulin levels occurs to some extent in most adults as they age, and increases as body fat increases. A diagnosis of diabetes occurs only at the end stage of this process, which exists for many years before blood sugar elevates.

Elevated levels of blood insulin contribute to diseases of aging in other ways.

Deep Sleep is Necessary for Normal HGH Production

Release of HGH occurs primary during the early hours of sleep and is directly proportional to the time spent in deep, slow-wave sleep. Time spent in slow-wave sleep decreases with age, and parallels decrease of HGH release into the circulation.

Sex Hormones are Synergistic with HGH, Cortisone is Antagonistic

Sex hormones at youthful levels (estrogen/progesterone and testosterone)  potentiate benefit from HGH. Those hormones work synergistically to reinforce each other.

Corticosteroid hormones one block benefit from HGH. Cortisone production gradually increases with age in most people. This is not desirable. HGH secretogogues also increase cortisone production, which makes an undesirable situation worse.

Some types of secretogogues increase cortisone production disproportionately, which may deceptively enhance a sense of well being, while speeding the aging process and depressing immunity.

BENEFITS OF HGH OCCUR SLOWLY

Benefits of HGH replacement occur slowly and gradually during the first 6 months of therapy. Some benefits, such as reversal of osteoporosis and increased muscle mass, do not significantly improve until after 6 to 18 months of therapy.

HGH DECLINES MOST RAPIDLY BEFORE AGE 45

HGH does not decline at a steady 14% per decade as previously thought. Decline in HGH production is more rapid between adolescence and age 40 to 45. Between the ages of 40 and 50 most of the decline in HGH has already occurred, although that decline continues at a slower rate into later life. On the average IGF-1 declines from 260 at age 20 to 120 at age 45, more than a 50% decline. The decline then continues to an IGF-1 level of 50 or less by age 85. (These are averages with significant individual variability.)

HGH replacement therapy results in lower LDL cholesterol and reduces tissue leptin resistance. Leptin controls fat metabolism.

HGH replacement was given in medical school research studies when IGF-1 was 200 or less and testosterone levels were 300 or less. One medical school professor of endocrinology stated from the podium that, based on recent research, he recommends HGH replacement with age.

Recent studies show that the dose of HGH to produce optimum benefit is between 1 and 2 units every day, depending on body size. One to 1½ units daily seems to be the most effective dose, although significant benefits do occur with as little as 4 units weekly. Side effects were mild and transient at those doses, and diminished with continued therapy.

Studies in which significant side effects were reported used more than 2 units daily, and sometimes as much as 15 units daily, which is a serious overdose.

Most recent thinking is that one unit of HGH daily at bedtime is an effective dose with minimum chance of side effects. That is close to the same amount produced by a youthful pituitary gland. A dose of 1½ unit was also safe and increases benefit somewhat. Two units daily is recommended only for large people.

Recombinant hypothalamic growth hormone releasing hormone (rGHRH) does not give the same benefits as HGH. A recent study at the University of Colorado Medical School using rGHRH showed only minor benefits. A larger dose might have been more effective, until tolerance developed, but the cost would have been much greater than HGH. All such secretogogues gradually lose effectiveness after a few months of use (increasing tolerance), even purified rGHRH, HGH releasing peptide (GHRP), and the Merck experimental oral secretagogue, MK-677.

BODY FAT ACTS TO DECREASE HGH RELEASE BY THE PITUITARY

As body fat increases, HGH secretion decreases. Body fat itself decreases HGH production, independent of age. In addition, increasing body fat decreases the effectiveness of HGH. So increasing fat has a doubly adverse effect on HGH.

Decline in HGH is mainly related to abdominal, visceral fat (mid to lower abdomen, including mesenteric fat surrounding the intestines).

Exercise increases responsiveness to HGH and increases release of HGH by the pituitary gland, but that effect declines with age.

Only three significant variables have been found by extensive research to predict 24-hour HGH release by the pituitary gland. HGH is present in the blood for a very short time and is produced in short pulses. To accurately assess HGH release it is necessary to keep a catheter in a vein and take blood every few minutes over 24 hours, measuring HGH on every specimen. That is not practical in a clinical setting, but that is how this study was done. Those things that correlated best with such direct measurement of HGH:

The strongest correlation was the amount of abdominal visceral fat, independent of age. The next strongest correlation was that HGH decreases inversely with higher fasting serum insulin levels (i.e., loss of tissue sensitivity to insulin with increasing blood insulin levels and carbohydrate intolerance decreases HGH release by the pituitary).

Blood levels of IGF-1 (somatomedin-C) remain the most practical laboratory test to predict pituitary release of HGH in a clinical setting.

It is postulated that abdominal visceral fat leads to more insulin resistance, elevated blood insulin levels, which in turn act to inhibit the hypothalamus in the base of the brain, uncoupling HGH release.

Perhaps insulin acts to displace IGF-1 from its binding protein, allowing more free IGF-1 to feed back negatively on the hypothalamus? Insulin and IGF-1 have similarities. Perhaps insulin acts to block or otherwise affect IGF-1 receptors.

Both HGH and IGF-1 decline with age. That decline leads to an increase in abdominal visceral fat, which in turn causes more insulin to be produced. Increasing insulin reduces HGH, creating a cycle that reinforces itself, a so-called vicious cycle.

Exercise helps to lower insulin levels and slows this process. Less simple sugars and less dietary intake of the type of carbohydrates producing the insulin should also help.

SEX HORMONES, HGH, IGF-1 and CANCER

HGH and IGF-1 do not promote cancer. There are many large studies to document that fact. Patients with acromegally, who have a pituitary tumor producing massive amounts of HGH, do not have a significantly increased incidence of cancer. Cancer patients who have had surgery or radiation to destroy the pituitary and then get HGH replacement don’t have an increased incidence of cancer recurrence. Children with pituitary dwarfism who get HGH replacement for normal growth do not have an increase in childhood cancer. One large study of patients receiving HGH by injection for age-related decline in HGH did not show any increase in cancer.

It’s true that IGF-1 blood levels correlate with the incidence of cancers of the sex hormone-dependent organs, (prostate and breast). But that’s because the sex hormones do not have an effect without IGF-1. Presence of IGF-1 is necessary for estrogen and testosterone to have their effect. IGF-1 by itself does not have any effect on cancer. But a sex hormone-dependent cancer (breast or prostate) can be slowed by depriving it of testosterone or estrogen. That can be accomplished therapeutically with surgical castration or also by chemically blocking sex hormone effect (Lupron or Tamoxifen). Deficiencies of IGF-1 also act to reduce the effectiveness of sex hormones on hormone-dependent cancers. Low IGF-1 therefore has an effect similar to castration. That may be desirable if a hormone-dependent cancer is present, but most adults would prefer not to become eunuchs merely because of the aging process.

There’s a big difference in finding that a cancer can be slowed by depriving it of a factor it needs for growth and, on the other hand, stating  hormones cause cancer. Many organs in the body require hormones for healthy function. HGH does not cause or increase the growth of cancer in any study thus far. Testosterone replacement in men and estrogen replacement in women do not cause cancer by themselves in studies done so far. Even the studies allegedly relating estrogen replacement and breast cancer are open to interpretation. But, if such a cancer is present, its growth can be slowed by a deficiency of a necessary hormone.

HGH is also not as effective if testosterone or estrogen is low. They work together synergistically. It works both ways.

INSULIN RESISTANCE DEVELOPS AT THE CELL LEVEL WITH AGE

High insulin levels lead to increasing abdominal visceral fat, which leads to elevated blood triglycerides, elevated LDL cholesterol, and adverse total cholesterol to HDL cholesterol ratio.

Exercise improves tissue response to insulin (and probably other peptide hormones) and acts to reverse or partially reverse this process at its cause.

TELEOMERS ON CHROMOSOMES

Until recently telomers were thought to be simple counters on chromosomes (meters) that counted down to zero, causing cell replication to stop when they were gone, like plucking a bead off a string with each cell replication. It’s now known that telomers are also potent modulators of gene expression.

As telomers become shorter with age, cells become increasingly senescent. Long before telomers are gone, gene expression is impaired and cells deteriorate. The enzyme, telomerase, can regenerate shortened telomers. Cells might thus be rejuvenated by the enzyme telomerase when they become senescent but are still viable. Research is underway to find a way to get teleomerase safely into aging cells without causing uncontrolled growth and malignancy. Cancer cells also produce telomerase, which is one reason why they reproduce in an uncontrolled way. But other cells containing telomerase are known to reproduce indefinitely without becoming malignant—so-called immortal cells, including the germ cells in ovaries and testes.

Healthy telomerized old skin cells become young skin in laboratory cell-culture experiments. Impaired gene expression caused by gradual loss of telomers with age is now thought to be more important than total loss of telomers.

Mitochondrial free radical production increases with age to produce the same amount of ATP (cell energy). Increased anti-oxidant protection is therefore needed with aging to protect cell constituents.

MELATONIN

Patients with atherosclerosis have lower average melatonin levels. Many research studies show that victims of coronary artery and cardiovascular disease produce less melatonin.

CIRCADIAN CYCLES AND SUN SPOT CYCLES

Hormone levels and other physiologic functions such as heart rate and blood pressure have been shown to vary not just with 24-hour circadian cycles but also with 7-day cycles and even 11- and 22-year sunspot cycles.

MENOPAUSE

Women with surgical menopause following removal of their ovaries benefit from small-dose testosterone replacement combined with estrogen (not by itself). Testosterone improves mood and psychological symptoms more than estrogen. Progesterone helps slow-wave sleep. Only estrogen helps hot flushes, which occur in 80% of menopausal women.

ADRENOPAUSE AND DHEA

DHEA declines with age. Cortisone increases with age. The age-related changes in both of those hormones add to undesirable symptoms of aging.

DHEA replacement (in the range of 50 mg daily) brings the following benefits in research studies:

->Improved ability to cope

->Improved mobility

->Improved sleep

->Less pain

->Increased sex drive

->Slightly increased IGF-1

->Increased muscle strength

LEPTIN

In a lifetime, we eat 50 million calories and 36,000 pounds of food. But on the average, we gain only 50 pounds. It’s a very fine balance. Just a tiny imbalance can lead to weight gain.

Food intake decreases with age, despite weight gain, which indicates more efficient conversion of calories to fat. Metabolism is less efficient at burning calories with age. Also, as insulin goes up, calories are more easily stored as fat and are more difficult to burn. Weight increases on the average by one pound per year in adults until the mid to late 70’s and then decreases somewhat as tissues atrophy, with considerable individual variability.

LEPTIN, a newly discovered fat-related hormone, is released from fat cells. It signals the brain to reduce appetite (eat less) and burn more energy. It uncouples mitochondrial energy production, producing heat rather than fat.

Leptin is one regulator of the process, but leptin is 5 times more effective in the young than the elderly. Like insulin, leptin sensitivity declines at the cell level with age. This is not totally understood and is a very complex and interrelated phenomenon. It’s known that high levels of insulin needed to control blood sugar in adult-onset diabetes also accelerate other diseases while it controls glucose. There’s preliminary evidence that leptin may cause similar problems.

SURGICAL HEALING

One clinical study in Holland reported that when elderly patients were given HGH replacement after hip surgery, their hospital stays were shortened and they returned to activities of daily life more quickly. Those patients not given HGH suffered 25% more long-term disability. The amount of money for long-term medical care and disability that could have been saved by HGH replacement more than equaled the total annual medical research budget for that country.