Books in Progress
The Molecular Biology of Free Radicals: Their roles in cell signaling, disease, and aging
Molecular oxygen and nitrogen present a paradox to aerobic organisms: they are both essential and potentially toxic because of the free radicals produced from them. Indeed, it is now clear that aging and many diseases are attributable to these free radicals, whcih are generated from inside of cells. These free radicals are formed from oxygen and nitrogen, either alone or together, and are referred to as reactive oxygen species (ROS) or reactive nitrogen species (RNS). Excess ROS and RNS are capable of oxidizing and damaging proteins, nucleic acids, polysaccharides, and lipids. In addition, high intracellular levels of either can affect the redox state levels of glutathione and thioredoxin, cofactors for anti-oxidant enzymes. Collectively, the excess accumulation of ROS or RNS and the uncontrolled oxidation of cellular components by ROS and/or RNS is referred to as oxidative stress. Excess RNS can also affect the inappropriate nitrosation or nitrosylation of cellular targets including proteins and glutathione. This is referred to as nitrosative stress. Oxidative and nitrosative stress accompany aging and several diseases including hypertension, cardiovascular disease, ischemia-reperfusion injury, atherosclerosis, diabetic peripheral neuopathies, cancer, Alzheimer's disease, and a variety of other dementias. Many of these diseases are also related to chronic or acute stress, other inducers of ROS production.
Although much of the research on ROS and RNS has focused on their deleterious effects, recent studies have demonstrated that low to moderate levels of each act as important physiological signals for a variety of cellular and developmental processes and are crucial for survivial. These paradoxical roles of ROS and RNS have raised a number of important questions that are addressed in this book. These are:
- Are ROS or RNS produced under hypoxic or anoxic conditions and, if so, how?
- Where in a cell are ROS and RNS produced?
- How are the levels of ROS and RNS controlled?
- How do cells and tissues deal with the damage caused by oxidative and nitrosative stress?
- How do ROS and RNS function in cell signaling and how specific are they?
- What can be done to mitigate free radical damage without affecting their role in cell signaling?
- How do free radicals contribute to disease and aging?
The Paradox of Aging: What science has taught us about longevity and the aging process
Human life expectancy is increasing throughout the world. During the 20th century, life expectancy at birth in the United States increased from 47 years to over 76 years, and is expected to continue rising. This rise in life expectancy has had a substantial societal impact. Indeed the increasing numbers of 'senior' citizens has raised questions about the future of social security, the costs of medicare, and the housing of our elderly. It has also driven new research on aging and has led to a flurry of questions cconcerning longevity and how we might increase it even more:
- Is the body a machine that simply wears out; if so, why do some cells seem immortal?
- What can we learn from the fact that different animals afe at different rates?
- What cellular and biochemical processes cause aging and the degenerate diseases associated with it?
- Is there a gene for aging; will we be able to control it?
- Are there such things as anti-aging drugs or supplements?
These questions are not new. Indeed, the fear of aging has pre-occupied mankind since the beginning of time. It has driven the quest for the 'fountain of youth' and has spurred numerous quack remedies and fraudulent claims for extending lifespan. With the advent of the tools of molecular biology and modern genetics, this quest to understand aging and extend lifespan has given way to serious scientific investigation, which has yielded important clues about the aging process. In this book, I will review what is known about the biology of aging. First we will consider the natural history of aging and will take a look at some of the ideas put forward by early alchemists, the rejuvenation and organ replacement 'therapies' used in the 19th century, and the hormone replacement 'therapies' of the 20th century. These will be considered in the context of the relationship between aging and reproduction. We will then analyze some general theories of aging, emphasizing the evolutionary theory of aging. Using recent findings from modern molecular biology, genetics, and biochemistry, the book will then take a look at the processes that cause aging and degenerative diseases. Finally, I will examine some theories on how to mitigat the aging process.
What About the Mitochondria? How these unusual cell structures affect your health, aging, and longevity
One of the major challenges of modern biology is to understand how and why we age. Although aging is certain to be driven by multifactorial processes, it is now clear that it starts in cells and then progresses to tissues and organs, and finally to the individual. The aging process within cells starts in the mitochondrion, an unusual thread-like structure, which is at the causal epicenter of aging and many age-related degenerative diseases. Mitochondria contain their own genome (mtDNA), which communicates with the nuclear genome (nDNA) via a variety of distinct signaling pathways. Although mitochondria have long been known to be the source for most of the chemical energy generated by eukaryotic cells, recent research has revealed that they play a multitude of additional roles in normal cell function and in the pathophysiologies associated with the degenerative diseases of aging. These functions include:
- Oxygen sensing and the regulation of oxygen sensitive nuclear gene expression
- The generation of free radicals that contribute to aging
- The lifespan extension that results from limiting caloric intake
- Inflammation and the development of the inflammasome
- The initiation of programmed cell death during development
- Calcium homeostasis
- Cell growth and division
- Maintenance of vascular health
- Protection against many types of dementia
Most of these roles involve signaling molecules that leave the mitochondrion and exert their effects on metabolism of the expression of nuclear genes. These 'signals' include reactive oxygen species (ROS), reactive nitrogen species (RNS, including nitric oxide and peroxynitrite), NAD/NADH, ATP, calcium, and heme. They may also include small peptides encoded within the ribosomal genes on mtDNA in a pathway that we have named intragenomic signaling.
As a result of these new findings, it now appears that the mitochondrion is the 'environmental stress sensor' within cells that senses and responds to changes in the environment. It is in its capacity as the 'environmental stress sensor' that the mitochondrion plays a pivotal role in aging. To understand how the mitochondrion participates in aging and disease, it is useful to take a look at mitochondrial biology, genetics, and biochemistry. Some of the questions addressed in this book are:
- How did mitochondria and mtDNA evolve?
- What roles do mtDNA and nDNA play in the formation (biogenesis) of mitochondria?
- How do mtDNA and nDNA communicate with each other?
- What causes mitochondria to be dynamic structures?
- Why do mitochondria undergo fission and fusion?
- How do mitochondria produce energy from the food that we eat?
- What causes the mitochondrion to release ROS, RNS, and other molecules in response to stress?
- Are mitochondrial genes on mtDNA passed from generation to generation?
- Do both parents contribute equal amounts of mtDNA to their offspring?
- How does the mitochondrion affect our longevity and age-related diseases?