Medical Causality

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

One of the points discussed in the book is disease causation, and how we often fool ourselves into thinking that we understand how a disease develops, simply because we can name the gene or agent that precipitates the disease.

Here is an excerpt from Chapter 8 [Note: Pathogenesis is the sequence of cellular events that eventually leads to the clinical expression of a disease. Pathogenesis, when restricted to cancer, is known as carcinogenesis.]:

In the field of medicine, we often cannot assign a specific cause to a particular disease without seriously misleading ourselves. For example, what is the cause of rheumatic fever? Rheumatic fever is an autoimmune process that targets the heart. Rheumatic fever occurs in people who have been infected with a Group A strain of Streptococcus pyogenes. The infection, which usually presents as a pharyngitis, elicits an immune response against a bacterial antigen. The antibody species that target the bacterial antigen happen to cross-react with proteins in normal heart and vessels. These cross-reacting antibodies damage the heart and vessels to produce rheumatic fever.

Rheumatic fever is one of the most thoroughly studied and best understood diseases known to man. Knowing all that we know about the pathogenesis, pathology, and clinical features of rheumatic fever, it should be easy to specify the cause of the disease. Alas, this is not the case. For example, we cannot assert that rheumatic fever is caused by Streptococcus pyogenes because not all cases of infection lead to rheumatic fever, and because the clinical features of the disease are not actually caused by the infection. Likewise, we cannot assert that rheumatic fever is an autoimmune disease because it does not result from a defect in the autoimmune response. Basically, rheumatic fever involves a normal immune response to a foreign antigen (i.e., a protein of Streptococcus pyogenes bacteria) that happens to cross-react with the heart proteins. Furthermore, we cannot claim that rheumatic fever is caused by a heart defect; the heart is an innocent bystander in a process that evolved over time in tissues other than the heart (i.e., the pharynx and other tissues in which immunocytes reside). The more we know about the pathogenesis of rheumatic fever, the more difficult it becomes to specify its cause.

What applies generally in medicine will apply equally in the cancer field. Knowing the name of an oncogene that is always expressed in a particular type of cancer may be an important clue to understanding causation and pathogenesis, but it's never the whole story.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, orphan disease, orphan drugs, rheumatic fever, rheumatic heart disease, heart disease, immune disease, strep infection, causality, disease causation, cause of disease, pathogenesis

Common Cancers Have Rare Cancer Subsets

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

One of the key ideas developed in the book is that each common diseases is actually an aggregate of cellular processes that are present, individually, in rare diseases. In the case of the common cancers, we can find specific rare diseases that are subsets of the common diseases.

Here is an excerpt from Chapter 8:

8.3.3 Inherited syndromes that cause rare cancers are often associated with increased risk for developing common cancers; hence, the causes of rare cancers are related to the causes of common cancers. Many of the greatest advances in our understanding of common cancers have come through the study of rare familial cancer syndromes in which common types of cancer occur. Here are a few common cancers and the familial syndromes that account for a small percentage of cases.

Colon tumors (benign and malignant)

- Colorectal cancer hereditary non-polyposis
- Polyposis syndrome, mixed hereditary
- Turcot syndrome (central nervous system cancer and familial polyposis of the colon)
- Mismatch repair gene pmsl1 colorectal cancer hereditary, non-polyposis type 3 included
- Checkpoint kinase 2 S. pombe homologue of breast and colorectal cancer susceptibility
- Colorectal adenomatous polyposis autosomal recessive
- Oligodontia–colorectal cancer syndrome
- Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
- Adenomatous polyposis of the colon (APC)
- Peutz–Jeghers syndrome
- Colorectal cancer hereditary non-polyposis type 2
- Colorectal cancer susceptibility on chromosome 9

Lung cancer

- Lung cancer 1
- Lung cancer, alveolar cell carcinoma included

Breast cancer

- Brca1 breast cancer type 1
- Breast cancer 11–22 translocation associated
- Brca2 breast cancer type 2
- Brca3 breast cancer type 3

Basal cell carcinoma of skin (see Glossary item, Basal cell carcinoma)

- Basal cell carcinomas with milia and coarse sparse hair
- Basal cell nevus syndrome
- Basal cell carcinoma, multiple
- Basaloid follicular hamartoma syndrome (see Glossary item, Hamartoma)
- Basal cell carcinoma with follicular differentiation
- Xeroderma pigmentosum complementation group b
- Xeroderma pigmentosum 1

Renal cell carcinoma

- Renal carcinoma, familial associated 1 included
- Renal cell carcinoma, papillary
- Non-papillary renal carcinoma 1
- Renal cell carcinoma, papillary 3
- Leiomyomatosis and renal cell cancer hereditary

Thyroid cancer

- Thyroid carcinoma, familial medullary
- Familial non-medullary thyroid cancer
- Papillary thyroid microcarcinoma
- Thyroid carcinoma, papillary with papillary renal neoplasia
- Thyroid carcinoma, non-medullary 1
- Thyroid carcinoma, Hürthle cell
- Thyroid carcinoma, follicular

Ovarian cancer

- Epithelial ovarian cancer
- Ovarian cancer, epithelial, susceptibility to

Melanoma

- Melanoma, cutaneous malignant 4
- Melanoma, cutaneous malignant 3
- Familial atypical multiple mole melanoma-pancreatic carcinoma syndrome
- Dysplastic nevus syndrome, hereditary b-k mole syndrome

Prostate cancer

- Prostate cancer, hereditary x-linked
- Prostate cancer, hereditary 1
- Prostate cancer, hereditary 20
- Prostate cancer, hereditary 7
- Prostate cancer, hereditary 3
- Prostate cancer/brain cancer, susceptibility

When we look at individual inherited cancer syndromes, we see that both rare and common cancers may result. Here is the list of different types of cancer associated with the Li–Fraumeni syndrome [15]. The syndrome-associated cancers are divided into common and rare cancers.

Common tumors associated with Li-Fraumeni syndrome

- Breast cancer
- Lung adenocarcinoma
- Colon cancer
- Pancreatic cancer
- Prostate cancer

Rare tumors associated with Li-Fraumeni syndrome

- Soft tissue sarcomas
- Osteosarcomas
- Brain tumors
- Acute leukemias
- Adrenocortical carcinomas
- Wilms tumor
- Phyllodes tumor of breast

It is worth noting that the common cancers associated with rare cancer syndromes have a similar morphologic appearance as their sporadic counterparts. This suggests that regardless of underlying genetic cause, the pathogenesis of each named common cancer tends to converge to its characteristic phenotype.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, orphan disease, orphan drugs, carcinogenesis, common cancers, rare cancers, cancer syndromes, familial cancer syndromes

Cancer Research: A Decades-old Approach that has not Worked

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Here is a short excerpt from Chapter 8:

Though there are thousands of types of human cancer, the bulk of cancer cases in humans are accounted for by just a few, under a dozen, types of cancer. The two most commonly occurring cancers of humans are basal cell carcinoma of skin and squamous cell carcinoma of skin. Together, these two tumors account for about 1.2 million new cancers each year in the U.S., nearly equal to the number of all the other types of cancers combined. These tumors are so common that, frequently, more than one basal cell carcinoma or squamous cell carcinoma will occur in the same individual. Fortunately for us, these two tumors seldom cause deaths; most cases are cured by simple excision. Cancer registries do not bother to collect records on these two cancers, and the published data on cancer incidence, compiled from registries and surveillance databases, typically ignores these two tumors. Nonetheless, we will see later in this chapter that basal cell carcinoma of skin and squamous cell carcinoma of skin tell us much about the biology of cancer in humans.

In Section 2.1, we discussed Pareto’s principle, wherein a few common items account for the majority of instances of any collection. Cancer obeys Pareto’s principle: a few cancers account for most cases of cancer occurring in humans. Collected U.S. data for the year 2008 indicate that, after excluding basal cell carcinomas and squamous cell carcinomas of skin, there were 1,437,180 new cancers. In the same year, there were 565,650 cancer deaths, of which 161,840 individuals died of lung cancer [1]. The percentage of U.S. cancer deaths from lung cancer was 28.6% (161,840/565,650). Also in 2008, there were 49,960 deaths from colorectal cancer, accounting for 8.8% of U.S. cancer deaths (49,960/565,650). Just two cancers (lung and colorectal) accounted for 37.4% of deaths from cancer in the U.S. When age-adjusted data are examined, the top five cancer killers (lung, colon, breast, pancreas, and prostate) account for 57% of all cancer deaths [1] (see Glossary item, Age-adjusted).

Observing that a few types of cancers account for the bulk of human cancer deaths, funding agencies have concentrated their efforts on finding cures for the most common cancers. Just seven types of common cancer, out of about 6000 known cancers, account for over 36% of cancer funding [2]. The justification for distributing cancer research funding toward research in the common cancers is simple. If cures can be found for the most common cancers, we could drastically reduce the number of cancer deaths in the U.S. and in the world. Curing a rare cancer that might affect a few hundred people worldwide would seem to be an ill-advised investment of our limited resources. Hence the rare cancers receive relatively little cancer funding compared with the common cancers.

The drawback to this straightforward approach is that it has failed. Despite decades of funding, we still do not know how to cure common cancers when they are diagnosed at an advanced disease stage. New discoveries in cancer genetics have highlighted the incredible complexity of the commonly occurring cancers. The complexity of the common cancers has been a seemingly insurmountable barrier blocking the development of simple and effective cures. Despite the long-term efforts of an army of cancer researchers, the age-adjusted death rate from cancers in the year 2000 was about the same as it was in 1975. A significant drop in the cancer death rate since the year 2000 is largely attributed to smoking cessation and other preventive measures; not due to effective new cures for the advanced stage common cancers[3].

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, orphan disease, orphan drugs, advanced stage cancer, ineffective cancer research, advanced stage cancers, cancer priorities, cancer funding, cancer research funding

Blog Posts on Rare Diseases and Orphan Drugs

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Over the past several weeks, I've been writing to several different blog sites on the subject of rare cancers. Here is a list of my rare disease posts, with links:

Developing Diagnostic Tests for Common Diseases: Role of the Rare Diseases

Rare Diseases Account for Subsets of Common Diseases

Phenocopy Mimics of Rare Diseases: Lessons for the Common Diseases

Phenocopy Diseases: Their Relationship to Rare Diseases and Common Diseases

What Rare Diseases Teach Us About the Cellular Basis of Aging

What is the Fundamental Biological Process that Causes Aging?

Wrinkling and Sagging are Chronic Toxic Processes Not Directly Caused by Aging

Disease Complexity: Rare Diseases and Common Diseases

Case Reports of Rare Diseases Have General Value

When Rare Diseases and Common Diseases Converge to Same Clinical Picture

Rare Diseases and Common Diseases can Converge to the Same Clinical Conditions

Rare Disease Legislation in the U.S.

Definition of Rare Disease

Developing Diagnostic Tests for Common Diseases: Role of the Rare Diseases

Rare Diseases Account for Subsets of Common Diseases

Improving Clinical Trials by Focusing on Rare Diseases

Rare Diseases of Unknown Origin

Rare Diseases are Sentinels for the Common Diseases

Biological Differences between Rare Cancers and Common Cancers

Rare Diseases are Biologically Different from Common Diseases

Rare Cancers are Biologically Different from Common Cancers

Rare Cancers

Clinical Trials and Rare Diseases

Rules for the Rare Diseases

The Rationale for Funding Rare Disease Research

New Book Explains the Importance of Rare Disease Research

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you think that you and your colleagues may benefit from reading this book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

tags: rare diseases, orphan diseases, orphan drugs, funding opportunities, rare cancers, common diseases, complex diseases, clinical trials, rare disease organizations, disease advocates

Acquired Diseases that Replicate the Defect of Genetic Diseases

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Phenocopy diseases are medical conditions that closely mimic a genetic disease, but are caused or triggered by an environmental factor. In many cases, phenocopy diseases are non-hereditary and acute. In some cases, the phenocopy disease is reversible when the environmental trigger is removed or when an appropriate treatment is applied.

Here is just one example of phenocopy disease (from my book):

Acquired conduction defect [the phenocopy disease] and inherited conduction defect [the rare, genetic disease that is copied by the phenocopy disease]

Disorders of the electrical systems in humans that defects of ion flux across membranes are known as channelopathies. The inherited cardiac conduction channelopathies were discussed in Section 5.3.

Because the anti-arrhythmogenic and anti-epileptic drugs typically target ion channels, they are the drugs most likely to produce, as an adverse side effect, disorders of cardiac conduction. For example, rufinamide, an oral antiepileptic drug, has been reported to cause QT-interval shortening [44]. Quinidine, disopyramide, and procainamide have been reported to produce QT prolongation [45].

Several channelopathies can be acquired as autoimmune diseases, in which antibodies react with ion channels, or related cellular components upon which the ion channels depend (e.g., myasthenia gravis, Lambert–Eaton myasthenic syndrome, cerebellar ataxia associated with VGCC antibodies, acquired neuromyotonia, Morvan fibrillary chorea, limbic encephalitis) [46].

Progressive familial heart block type IA is a genetic disorder of the cardiac conduction system. Clinically similar conditions can be acquired when the tissues of the conduction systems are damaged, as in: myocardial infarct, conduction system ischemia (i.e., lack of blood flow to components of the conduction system, particularly the His–Purkinje conduction tissue), age-related degeneration of conduction system, and complications of procedures (i.e., insertion of wires or lines into the heart chambers) [47].

In a similar fashion, there are some types of cancer that can have a genetic cause or an environmental cause (or both). For example, most lung cancer occurring in humans has an an acquired, environmental cause (i.e., smoking). Some cases of lung cancers are genetic (i.e., inherited NUT gene mutation in midline lung carcinoma of the young). The importance of the phenocopy diseases (acquired near-equivalents of rare genetic diseases) to our general understanding of cancer, and to the successful treatment of rare cancers and common cancers, is discussed in my book.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, orphan disease, orphan drugs, phenocopy disease, complex disease, heart block, arrhythmia, disease biology, cancer, carcinogenesis, acquired cancer, environmental cancer, rare cancer, common cancer

Aging and Cancer: Two Diseases of Cellular Renewal

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Chapter 4 explains that much what we think we know about the aging process comes from studying rare diseases of premature aging, such as Hutchinson–Gilford progeria syndrome, Bloom syndrome, Werner syndrome, Cockayne syndrome, dyskeratosis congenita, Fanconi anemia, Wolfram syndrome, and xeroderma pigmentosum. Lessons learned from these rare diseases are summarized in Chapter 4.

From Chapter 4:

4.4.3 Rule—On a cellular basis, aging is a process confined to non-renewable cell populations. Brief Rationale—Long-lived cells that cannot replace themselves, such as fully differentiated neurons, muscle cells, and cartilage cells, have no biological destiny other than degeneration and death.

As non-dividing cells undergo wear and tear, or suffer damage that cannot be repaired, they will die. The tissues in which these damaged cells reside will function with diminished capacity. For example, osteoarthritis is a chronic disease that occurs from repeated episodes of bone crunching on its cartilage cushion within joints. Osteoarthritis occurs primarily in weight-bearing joints, such as knees and hips. Over a lifetime, the cartilage is frayed and eroded. Injured chondrocytes do not divide, or they divide with insufficient zest to restore a normal cartilaginous cushion. As erosion of the cartilaginous lining continues, an inflammatory reaction develops in the joint. The inflammatory reaction produces pain, swelling, and associated clinical symptoms.

Consider oocytes. All of the oocytes that a woman will produce are present in utero, reaching a peak of about 7 million cells at 5 months’ gestation. After the peak is reached, about 3 months before birth, the oocytes begin to die; they are not replaced. The number of live oocytes declines until the number falls below a threshold of 1000, triggering menopause [28]. In this instance, as in every other example of human tissues undergoing aging, the process involves cells that cannot regenerate.

Frailty is a universal feature of old age. After the age of about 50, muscle mass gradually declines. The frailty associated with extreme aging is due, in part, to progressive sarcopenia. Muscle cells atrophy (i.e., reduce their size), die, and are not renewed. Frailty occurs because muscle cells were not designed to renew themselves continuously and indefinitely.

It was once thought that the brain cells you were born with are the same cells that you will die with; that brain cells do not divide. It is now known that regeneration (i.e., the growth of new neurons) occurs throughout life. This may be so, but new growth comes from reserve cells, not from fully differentiated neurons. Cell division cannot occur in a cell that becomes very large, like a neuron, and has appendages (i.e., an axon and dendrites) extending to and from other cells, sometimes over great distances (up to several feet in the case of motor neurons innervating foot muscles). Axons are ensheathed by a dependent network of periaxonal cells (i.e., oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system). Neurons are transfixed anatomically, and cannot round up to divide. Hence, the fully mature neuron has little or no regenerative opportunity. Consequently, many of the cellular changes that we associate with aging take place in neurons. The dementia that accompanies aging is due to the inability of injured neurons to repair or replace

The tauopathies are disorders wherein tau protein accumulates within neurons. Tau proteins are involved in the stabilization of microtubules in every cell throughout the body, but they accumulate to the greatest extent in the neurons of the central nervous system. If a fully differentiated neuron cannot clear its tau proteins, it will suffer progressive damage, leading to cell death. Though tau proteins are ubiquitous, the tauopathies always develop as neurodegenerative disorders. Examples of diseases in which tau proteins are found include: Alzheimer’s disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, dementia pugilistica, a form of Parkinsonism known as Lytico–Bodig disease or as Parkinson–dementia complex of Guam, a form of Parkinsonism linked to chromosome 17, frontotemporal dementia, frontotemporal lobar degeneration, Hallervorden–Spatz disease, lipofuscinosis, meningioangiomatosis, Pick’s disease, a rare tumor of neurons known as ganglioglioma [29], subacute sclerosing panencephalitis, lead encephalopathy, tangle-predominant dementia, and tuberous sclerosis.

Agin The prion diseases are another example of disorders that target non-dividing neurons. The term prion was introduced in 1982 by Stanley Prusiner [30]. Prions are the only infectious agent that contains neither DNA nor RNA. A prion is a misfolded protein that can serve as a template for proteins of the same type to misfold, producing globs of non-functioning protein, causing cells to degenerate. The site of greatest accumulation of prion protein is in brain cells. Though few scientists would consider prions to be organisms, living or otherwise, they are undoubtedly transmissible infectious agents. The most common mode of transmission of prion disease is through the consumption of brains of infected animals.

The cells of the body that are most vulnerable to prion disease are the neurons of the brain. The reason for the particular sensitivity of neurons to prion disease relates to the limited ability of neurons to replicate (i.e., to replace damaged neurons with new neurons), reconnect (to replace damaged connections between a neuron and other cells), and to remove degenerated cells and debris. There are five known prion diseases of humans, and all of them produce encephalopathies characterized by decreasing cognitive ability and impaired motor coordination. They are: Kuru, Creutzfeldt–Jakob disease, bovine spongiform encephalopathy (known in humans as new variant Creutzfeldt–Jakob disease), Gerstmann–Straussler–Scheinker syndrome, and fatal familial insomnia. At present, all of the prion diseases are progressive and fatal. Prions have been observed in fungi, where their accumulation does not seem to produce any deleterious effect, and may even be advantageous to the organism [31].

In Section 4.3, we listed the many causative mechanisms underlying the rare diseases of premature aging. Without exception, every disease of premature aging creates a defect in the normal process of cellular renewal. If we understood how to control and maintain stem cell renewal, a feat that nematodes seem to have mastered, then we might understand how to defeat the aging process. In Chapter 7, we will be discussing cancer, another disorder of cell renewal. Whereas aging is a disease of cells that cannot divide, cancer is a disease of cells that cannot stop dividing.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: carcinogenesis, cancer and aging, rare disease, common disease, aging, ageing, cell renewal, cancer, cause of aging, biology of aging, orphan disease, orphan drugs

Cancer and Aging are Both Diseases of Cellular Renewal

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

There is a relationship between aging and cancer. Whereas aging is a disease of cells that cannot divide, cancer is a disease of cells that cannot stop dividing. Both diseases involve the processes of cellular renewal. If we understood aging, we would probably understand cancer.

Chapter 4 tackles the subject of human aging. Much of what we know about the aging process comes from studying rare diseases of premature aging, such as Hutchinson–Gilford progeria syndrome, Bloom syndrome, Werner syndrome, Cockayne syndrome, dyskeratosis congenita, Fanconi anemia, Wolfram syndrome, and xeroderma pigmentosum. The relationship between a these premature aging syndromes and natural aging processes are discussed in Chapter 4. The chapter synthesizes an approach to understanding aging gained by understanding the biological pathways that lead to cell death and degeneration in non-dividing cell populations.

Here is an excerpt from Chapter 4,

4.1.1 Rule—We do not have a scientifically meaningful definition for the diseases of aging. Brief Rationale—We do not know the cellular basis of aging; hence, we cannot determine whether a disease qualifies as a disease of aging on a cellular basis.

The majority of the so-called diseases of aging are conditions that make individuals look like old persons, or they are conditions that happen to occur more often in elderly individuals than in young individuals. One of the few points that experts in the field of aging can agree on is that the aging process is complex; not caused by any single factor.

4.1.2 Rule—Aging is not caused by a single gene. Brief Rationale—If aging were caused by a single gene, you would expect rare occurrences of loss-of-function mutations of the gene, leading to instances of human immortality. Outside of science fiction, immortal humans do not exist.

Most of us gauge aging by looking for visible features that always seem to be present in older individuals, and that are absent in youth. For the most part, these signs have very little to do with the biological aging process. The most familiar example is wrinkling and sagging. Wrinkling is a condition producedby chronic exposure to ultraviolet (UV) light. Over time, UV light denatures the connective tissue in the dermis, producing a condition called senile elastosis or, more accurately, solar elastosis. Most of the skin changes associated with aging, such as cracking, leathery texture, and poor elasticity (i.e., the ability of skin to regain its flat, tight surface after being stretched or pinched), are the result of chronic UV toxicity.

The other obvious change observed in older individuals is skin sagging. In many individuals, this is most pronounced in the folds of skin that grow under the chin and down the neck. Sagging flesh on older individuals is due entirely to two phenomena. The first is skin growth; humans grow their skin throughout life. This skin accumulates to different degrees in different individuals, depending on their genetically determined propensities for skin growth.

The other phenomenon is gravity. Without the effects of gravity, our skin would grow evenly over our body contours. We develop pendulous skin at sites with the least skeletal support (e.g., under chin, under breasts, under our arms). The changes we see in the skin of older individuals are due to the chronic effects of UV light, skin growth throughout life, and gravity that occur over time. They are not fundamental features of biological aging, because they do not occur in the absence of toxic conditions.

Is there any evidence to support this claim? One piece of evidence lies in differences in skin damage among races. The heavily pigmented races have much less wrinkling than the less pigmented races, because they are better shielded from UV light. Yet there is no corresponding extension of life expectancy among the less-wrinkled races, suggesting that damaged skin is unrelated to the aging process. Aside from that, any elderly person can do a simple experiment that will doubtless settle the issue for them. Strip off your clothes and inspect the parts of your body that are not exposed to light and that are not hanging from an anatomic prominence. For some, this would be the lower back or the upper thigh. In almost every case, you will be gratified to learn that this region of skin is unwrinkled, youthfully elastotic (i.e., will snap back in place when pinched), and relatively flat. Aside from a bit of softness due to skin growth, there really is not much difference between these protected regions of skin in elderly individuals and in young individuals. At this point, you can put your clothes back on, if you wish.

If wrinkling and sagging are not part of the aging process, then what physiological processes characterize aging?

As with every common disease, the biological basis of human aging is best understood by examining rare diseases that involve the aging process.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, cancer, aging, orphan disease, orphan drugs, cellular renewal, post-mitotic cell, wrinkling, sagging, uv light