Parkinson’s disease is a disorder of the basal nuclei, specifically of the substantia nigra, that demonstrates the effects of the direct and indirect pathways. Parkinson’s disease is the result of neurons in the substantia nigra pars compacta dying. These neurons release dopamine into the striatum. Without that modulatory influence, the basal nuclei are stuck in the indirect pathway, without the direct pathway being activated. The direct pathway is responsible for increasing cortical movement commands. The increased activity of the indirect pathway results in the hypokinetic disorder of Parkinson’s disease. Parkinson’s disease is neurodegenerative, meaning that neurons die that cannot be replaced, so there is no cure for the disorder. Treatments for Parkinson’s disease are aimed at increasing dopamine levels in the striatum. Currently, the most common way of doing that is by providing the amino acid L-DOPA, which is a precursor to the neurotransmitter dopamine and can cross the blood-brain barrier. With levels of the precursor elevated, the remaining cells of the substantia nigra pars compacta can make more neurotransmitter and have a greater effect. Unfortunately, the patient will become less responsive to L-DOPA treatment as time progresses, and it can cause increased dopamine levels elsewhere in the brain, which are associated with psychosis or schizophrenia.

Cerebrovascular accident, or stroke, is a common aging dysfunction that is often considered to be a dementia because it affects the brain.  The disease originates in the cardiovascular system when a blood vessel to the brain is obstructed or ruptures.  This cuts off blood flow to a region of the brain, causing the area to deteriorate and possibly producing permanent brain damage.  Large strokes may cause paralysis, dementia, or even death.  The death rates increase dramatically in individuals 65 years of age or older.

Urinary Incontinence

Urinary incontinence is the involuntary passing of urine through the urethra.  Between 30 and 50% of elderly people suffer from urinary incontinence.  Incontinence is caused by weakening of the urethral sphincters and the muscles of the pelvic floor.

Nocturia

Nocturia is defined as excessive urination at night.  While having to urinate multiple times in the night is not serious in itself it can contribute to insomnia.  Between 60 and 80% of people over the age of 65 experience nocturia.

Benign Hyperplasia

Benign hyperplasia is defined as the enlargement of the prostate gland.  The prostate gland is an organ of the male reproductive system.  When it enlarges the prostate gland puts pressure on the urethra.  Over time the increased pressure on the urethra makes it difficult for the bladder to be fully evacuated.  In sever cases urine can back up into the ureters and interfere with kidney functioning.

Carcinoma of the Prostate

Carcinoma of the prostate is the most common cancer in older men.  Over 50% of men over 70 years of age show signs of prostate cancer.  According to the Centers for Disease Control and Prevention (CDC), prostate cancer is the second most common cancer in men. However, some forms of prostate cancer grow very slowly and thus may not ever require treatment. Aggressive forms of prostate cancer, in contrast, involve metastasis to vulnerable organs like the lungs and brain. There is no link between BPH and prostate cancer, but the symptoms are similar. Prostate cancer is detected by a medical history, a blood test, and a rectal exam that allows physicians to palpate the prostate and check for unusual masses. If a mass is detected, the cancer diagnosis is confirmed by biopsy of the cells.

Pyelonephritis

Pyelonephritis is an inflammation of the kidney caused by a bacterial infection or viral infection.  The initial infection may be caused by a urinary tract infection, or travel to the kidney in the blood or lymph.  While the infections are generally easily treatable with antibiotics repeated infections can cause permanent scarring of the kidney tissue.  This affects the kidney function and can cause kidney failure.

Renal Calculi

Renal calculi, also know as kidney stones, become progressively more common with age.  The presence of stones in the kidney do not typically cause problems severe enough to be detected.  However, the passage of renal calculi from the kidney through the ureters, bladder, and urethra can be extremely painful.  Additionally the stones may become lodged in the ureter or cause ulcerations in the lining of the urinary tract.

Female Reproductive System

Female fertility (the ability to conceive) peaks when women are in their twenties, and is slowly reduced until a women reaches 35 years of age. After that time, fertility declines more rapidly, until it ends completely at the end of menopause. Menopause is the cessation of the menstrual cycle that occurs as a result of the loss of ovarian follicles and the hormones that they produce. A woman is considered to have completed menopause if she has not menstruated in a full year. After that point, she is considered postmenopausal. The average age for this change is consistent worldwide at between 50 and 52 years of age, but it can normally occur in a woman’s forties, or later in her fifties. Poor health, including smoking, can lead to earlier loss of fertility and earlier menopause.

As a woman reaches the age of menopause, depletion of the number of viable follicles in the ovaries due to atresia affects the hormonal regulation of the menstrual cycle. During the years leading up to menopause, there is a decrease in the levels of the hormone inhibin, which normally participates in a negative feedback loop to the pituitary to control the production of FSH. The menopausal decrease in inhibin leads to an increase in FSH. The presence of FSH stimulates more follicles to grow and secrete estrogen. Because small, secondary follicles also respond to increases in FSH levels, larger numbers of follicles are stimulated to grow; however, most undergo atresia and die. Eventually, this process leads to the depletion of all follicles in the ovaries, and the production of estrogen falls off dramatically. It is primarily the lack of estrogens that leads to the symptoms of menopause.

The earliest changes occur during the menopausal transition, often referred to as peri-menopause, when a women’s cycle becomes irregular but does not stop entirely. Although the levels of estrogen are still nearly the same as before the transition, the level of progesterone produced by the corpus luteum is reduced. This decline in progesterone can lead to abnormal growth, or hyperplasia, of the endometrium. This condition is a concern because it increases the risk of developing endometrial cancer. Two harmless conditions that can develop during the transition are uterine fibroids, which are benign masses of cells, and irregular bleeding. As estrogen levels change, other symptoms that occur are hot flashes and night sweats, trouble sleeping, vaginal dryness, mood swings, difficulty focusing, and thinning of hair on the head along with the growth of more hair on the face. Depending on the individual, these symptoms can be entirely absent, moderate, or severe.

After menopause, lower amounts of estrogens can lead to other changes. Cardiovascular disease becomes as prevalent in women as in men, possibly because estrogens reduce the amount of cholesterol in the blood vessels. When estrogen is lacking, many women find that they suddenly have problems with high cholesterol and the cardiovascular issues that accompany it. Osteoporosis is another problem because bone density decreases rapidly in the first years after menopause. The reduction in bone density leads to a higher incidence of fractures.

Hormone therapy (HT), which employs medication (synthetic estrogens and progestins) to increase estrogen and progestin levels, can alleviate some of the symptoms of menopause. In 2002, the Women’s Health Initiative began a study to observe women for the long-term outcomes of hormone replacement therapy over 8.5 years. However, the study was prematurely terminated after 5.2 years because of evidence of a higher than normal risk of breast cancer in patients taking estrogen-only HT. The potential positive effects on cardiovascular disease were also not realized in the estrogen-only patients. The results of other hormone replacement studies over the last 50 years, including a 2012 study that followed over 1,000 menopausal women for 10 years, have shown cardiovascular benefits from estrogen and no increased risk for cancer. Some researchers believe that the age group tested in the 2002 trial may have been too old to benefit from the therapy, thus skewing the results. In the meantime, intense debate and study of the benefits and risks of replacement therapy is ongoing. Current guidelines approve HT for the reduction of hot flashes or flushes, but this treatment is generally only considered when women first start showing signs of menopausal changes, is used in the lowest dose possible for the shortest time possible (5 years or less), and it is suggested that women on HT have regular pelvic and breast exams.

Male Reproductive System

As a result of the cumulative changes to the male reproductive system many men experience depression, mood swings, and a general feeling of uneasiness as they approach their 50s or 60s.  This time period is referred to as  andropause, or male menopause.  While the testes continue to function during and after this period men may experience impotence.  Regardless, even at advanced ages, some men are able to have sexual relationships and may even remain fertile.

Physiologically the testes decrease in size and firmness with age.  This is associated with a gradual age related decline in the secretion of testosterone.  Simultaneously there is a decrease in sexual desire.  By the age of 60 there is a 30% reduction in sperm count.  The prostate gland atrophies between the ages of 50 and 60 years of age, which reduces the secretory capacity.  By the age of 70 the prostate gland may enlarge due to masses of potentially cancerous tissue.  Additionally the seminal vesicles decrease in weight and storage capacity after age 60 and the penis undergoes some atrophy with age.

Cancer
Research over many years has confirmed that cervical cancer is most often caused by a sexually transmitted infection with human papillomavirus (HPV). There are over 100 related viruses in the HPV family, and the characteristics of each strain determine the outcome of the infection. In all cases, the virus enters body cells and uses its own genetic material to take over the host cell’s metabolic machinery and produce more virus particles.

HPV infections are common in both men and women. Indeed, a recent study determined that 42.5 percent of females had HPV at the time of testing. These women ranged in age from 14 to 59 years and differed in race, ethnicity, and number of sexual partners. Of note, the prevalence of HPV infection was 53.8 percent among women aged 20 to 24 years, the age group with the highest infection rate.

HPV strains are classified as high or low risk according to their potential to cause cancer. Though most HPV infections do not cause disease, the disruption of normal cellular functions in the low-risk forms of HPV can cause the male or female human host to develop genital warts. Often, the body is able to clear an HPV infection by normal immune responses within 2 years. However, the more serious, high-risk infection by certain types of HPV can result in cancer of the cervix. Infection with either of the cancer-causing variants HPV 16 or HPV 18 has been linked to more than 70 percent of all cervical cancer diagnoses. Although even these high-risk HPV strains can be cleared from the body over time, infections persist in some individuals. If this happens, the HPV infection can influence the cells of the cervix to develop precancerous changes.

Risk factors for cervical cancer include having unprotected sex; having multiple sexual partners; a first sexual experience at a younger age, when the cells of the cervix are not fully mature; failure to receive the HPV vaccine; a compromised immune system; and smoking. The risk of developing cervical cancer is doubled with cigarette smoking.

Development of Cervical Cancer
In most cases, cells infected with the HPV virus heal on their own. In some cases, however, the virus continues to spread and becomes an invasive cancer.

The left panel shows cell cycle. An arrow from the G2 phase leads to the right panel. The top half of the right panel describes the next steps in the absence of HPV and the bottom half describes the next steps in the presence of HPV.
When the high-risk types of HPV enter a cell, two viral proteins are used to neutralize proteins that the host cells use as checkpoints in the cell cycle. The best studied of these proteins is p53. In a normal cell, p53 detects DNA damage in the cell’s genome and either halts the progression of the cell cycle—allowing time for DNA repair to occur—or initiates apoptosis. Both of these processes prevent the accumulation of mutations in a cell’s genome. High-risk HPV can neutralize p53, keeping the cell in a state in which fast growth is possible and impairing apoptosis, allowing mutations to accumulate in the cellular DNA.

The prevalence of cervical cancer in the United States is very low because of regular screening exams called pap smears. Pap smears sample cells of the cervix, allowing the detection of abnormal cells. If pre-cancerous cells are detected, there are several highly effective techniques that are currently in use to remove them before they pose a danger. However, women in developing countries often do not have access to regular pap smears. As a result, these women account for as many as 80 percent of the cases of cervical cancer worldwide.

In 2006, the first vaccine against the high-risk types of HPV was approved. There are now two HPV vaccines available: Gardasil® and Cervarix®. Whereas these vaccines were initially only targeted for women, because HPV is sexually transmitted, both men and women require vaccination for this approach to achieve its maximum efficacy. A recent study suggests that the HPV vaccine has cut the rates of HPV infection by the four targeted strains at least in half. Unfortunately, the high cost of manufacturing the vaccine is currently limiting access to many women worldwide.

Atrophic Vaginitis
Atrophic vaginitis is inflammation of the vagina due to degenerative changes. This is dues to the age related thinning and dryness of the vaginal walls in postmenopausal women.

Prolapse of the Uterus
Prolapse of the uterus is a result of weakness of the ligaments supporting the organ. It is characterized by the uterus dropping through the cervical canal and protrudes into the vagina. Uterine prolapse may be corrected surgically or by the placement of a supportive instrument called a pessary in the vagina.

Impotence
Impotence, or Erectile dysfunction (ED), is a condition in which a man has difficulty either initiating or maintaining an erection. The combined prevalence of minimal, moderate, and complete ED is approximately 40 percent in men at age 40, and reaches nearly 70 percent by 70 years of age. In addition to aging, ED is associated with diabetes, vascular disease, psychiatric disorders, prostate disorders, the use of some drugs such as certain antidepressants, and problems with the testes resulting in low testosterone concentrations. These physical and emotional conditions can lead to interruptions in the vasodilation pathway and result in an inability to achieve an erection.

Recall that the release of NO induces relaxation of the smooth muscles that surround the penile arteries, leading to the vasodilation necessary to achieve an erection. To reverse the process of vasodilation, an enzyme called phosphodiesterase (PDE) degrades a key component of the NO signaling pathway called cGMP. There are several different forms of this enzyme, and PDE type 5 is the type of PDE found in the tissues of the penis. Scientists discovered that inhibiting PDE5 increases blood flow, and allows vasodilation of the penis to occur.

PDEs and the vasodilation signaling pathway are found in the vasculature in other parts of the body. In the 1990s, clinical trials of a PDE5 inhibitor called sildenafil were initiated to treat hypertension and angina pectoris (chest pain caused by poor blood flow through the heart). The trial showed that the drug was not effective at treating heart conditions, but many men experienced erection and priapism (erection lasting longer than 4 hours). Because of this, a clinical trial was started to investigate the ability of sildenafil to promote erections in men suffering from ED. In 1998, the FDA approved the drug, marketed as Viagra®. Since approval of the drug, sildenafil and similar PDE inhibitors now generate over a billion dollars a year in sales, and are reported to be effective in treating approximately 70 to 85 percent of cases of ED. Importantly, men with health problems—especially those with cardiac disease taking nitrates—should avoid Viagra or talk to their physician to find out if they are a candidate for the use of this drug, as deaths have been reported for at-risk users.

Biology of Aging by Lumen Learning is licensed under a Creative Commons Attribution 4.0 International License, except where otherwise noted.