The Impact of Autophagy in
Health and Disease
A smoothly functioning cellular environment contributes to overall health and resistance to disease. Autophagy is a complex process that supports cellular health by clearing damaged cellular materials and invading microorganisms.
When damaged organelles, clumped/tangled proteins, or microbes interfere with cellular operations, autophagy identifies them as dangerous, then compartmentalizes them and breaks them down. Autophagy also allows the cell to auto-digest itself (i.e., “self-eat”) should starvation require emergency nutrients. See Figure 1 for a simple illustration of how autophagy functions.
Autophagy is implicated in numerous diseases (see sidebar for examples) because suboptimal cellular function weakens the body’s defenses on several fronts. Autophagy stimulation can thus restore or enhance cellular health and contribute to disease treatment, either alone or by synergizing with the standard of care.
Autophagy is stimulated when cells are invaded by bacteria or viruses; whereupon, the microbes are quickly encapsulated and destroyed by digestive enzymes. Autophagy also regulates innate immunity and moderates inflammatory responses to microbial invasion. In the case of some microorganisms, e.g., tuberculosis, autophagy is inhibited, allowing the bacteria to survive in the body for several years. Autophagy stimulants, such as those being developed by Biophagy, have a role in fighting such microorganisms.
Mitochondria are small, distinctive organelles that live in the cytoplasmic environment and generate most of the energy needed for cellular operations and survival. This is accomplished via a long series of oxidative/reductive chemical reactions that ultimately generate adenosine triphospate (ATP), a high energy storage molecule. As mitochondria age, their organizational structure tends to break down and the reactive oxygen species generated in creating ATP (superoxide, hydroxy radical, hydrogen peroxide) can leak into the cytoplasm, damaging DNA, cellular structures, and molecules needed for smooth functioning. In addition, as the body ages, the mitochondria become more “leaky” in general and can release these damaging molecules in greater quantities.
The autophagic process can recognize damaged mitochondria and pull them out of the cellular environment, digesting them into component molecules for recycling into healthy organelles and other structures. This provides an antioxidant safety net, protecting the cell from a variety of damage, including oncogenic DNA mutations and apoptosis (cell death).
Autophagy tends to slow with aging and has been related to a number of related conditions, including:
- Energy reduction
- Chronic joint pain
- Reduced immune responses and increased susceptibility to infectious disease
Agents that stimulate autophagy have been widely heralded as a panacea for the symptoms of aging although proof of concept for most autophagy stimulants is lacking rigorous evidence. This is easy to find in a laboratory model where multiple pathways can be separated out and painstakingly studied but transferring this knowledge to a clinical situation has been elusive. The challenge to the autophagy research community is to dissect out specific autophagy activities that respond to a therapeutic and make a solid connection in human clinical practice.
Biophagy is working on this aspect using rational design to target different autophagy pathways with known supplements (CellWatch™). This knowledge is being used to develop highly targeted autophagy stimulant products and to refine its library of patented drugs toward more specific targeting in aging and disease.
Because autophagy is primarily a homeostasis mechanism, it is sensitive to stress and will respond quickly to a number of cellular disruptions. Starvation, causing prolonged lack of nutrients, will prompt genes to signal an increase in autophagy aimed at digesting the cell’s own constituents or self-eating (the Greek phrase for which autophagy was named).
When people fast or engage in severe caloric restriction, a drop in insulin and glucose will trigger an increase in autophagy after 1-3 days. Although the cell may attack some of its own organelles, these tend to be malfunctioning ones that are rapidly cleared, releasing more materials for recycling. Cells can then operate more efficiently and use less energy. An increase in general health plus resistance to infection and disease can result from such regimens. The robust health and longevity of cultures and individuals who practice caloric restriction on a long-term basis support autophagy’s role in overall health and aging.
Figure 1 shows a highly simplified diagram of the autophagy cascade:
- Unwanted materials (damaged organelles, clumped, denatured protein, invading microorganisms) are identified.
- They are encased in a vesicle that separates them from the cellular environment.
- This vesicle fuses with a lysosome containing acid-functioning enzymes that destroy the damaged materials, reducing them to subunit components for re-use.
Autophagy can reduce the build-up of toxic/damaged constituents in neurons leading to degeneration and loss of function. Many neurodegenerative diseases and conditions can be traced to suboptimal autophagy functioning resulting in serious diseases and disorders as listed below:
- Alzeheimer’s Disease
- Parkinson’s Disease
- Huntington’s Disease
- Amyotrophic lateral sclerosis
Autophagy is involved in immune recognition, the regulation of T cell maturation, and overall B and T cell homeostasis. It also affects inflammatory cytokines that can be positive or negative in various disease states. Autophagy has been implicated in many autoimmune diseases as listed below:
- Systemic lupus erythematosus
- Inflammatory bowel disease
- Rheumatoid arthritis
- Systemic sclerosis
- Multiple sclerosis
- Diabetic peripherial neuropathy
- Diabetic retinopathy
- Diabetic cardiomyopathy
- Obesity and metabolic syndrome
- Ischemic re-profusion injury
- Hepatitis B and C infection
- Deficiency of α -1-antitrypsin
- Chronic alcohol-induced cell death
- Liver fibrosis
- Anorexia nervosa
- Pulmonary fibrosis
- Pulmonary vascular disease
- Cystic fibrosis
Autophagy suppresses tumor growth in some cancers, especially in the initial stages but can also stimulate other cancers. Drugs that inhibit autophagy may be useful in selected diseases, e.g., pancreatic cancer.