- The History of Aging
- What We Know About Super Agers
- Longevity Research Is Still Young
- Lifestyle Secrets: Live Long and Prosper
- Centenarian Studies
- The Longevity Genes Project
- Strategies for a Longer Life
- Current Bodies of Research in Longevity
- Living Forever: The Research of Dr. Aubrey de Grey
- Cryonics: Freeze Me When I Die So I Can Live Forever
- Reports of Your Death Are Greatly Exaggerated
- Extendgame, Not the Endgame
Current Bodies of Research in Longevity
Longevity is a complicated field of scientific study because there is no single cause of aging. Sinclair said, “Our body functions better when we are young and better when we exercise and diet. Conversely, when we get old and more sedentary these genetic pathways are turned down and their ability to protect the body diminishes.”
He went on to explain there are four major areas of genetics currently being researched linked to longevity. They are:
The mTor pathway
The AMPK pathway
The following is a brief discussion of each of the four major areas of genetics, as well as the latest research pointing to a link in extending longevity. None of the genetic research has been applied to humans yet. All are still at an early stage of testing, which is why you’ll notice the studies only involve laboratory mice.
Sirtuins are proteins that regulate biological processes linked to aging. There are seven sirtuin genes and they’re found in different parts of the cells in the human body. Their functions include regulation of cell death as well as repair, insulin secretion, metabolic processes, and gene expression. Sinclair called sirtuins “protectors of cell health.”
The term Sir2 genes is used interchangeably with sirtuin. The name “Sir2” comes from the initial discovery of this group of genes. In the mid-1990s, the Sir2 gene was discovered by Dr. Leonard P. Guarente, a biology professor at MIT. His team (which included Dr. Sinclair, a graduate student at the time) was studying yeast cells to isolate potential longevity genes.
Guarente’s group split a group of the yeast cells up and removed the Sir2 gene from one of the groups. Both groups were fed a calorie-restricted diet. This stressed the cells and triggered the Sir2 gene. That gene expression halted the production of waste material in the cell, which allowed the cell to work more efficiently and for longer. The yeast cells lived longer than they should have.
Mammals, such as humans, don’t have Sir2 or (SIR2), but they do have SIRT1, which works in the same way, protecting cells by suppressing specific genes that when activated produce a malfunction in the cell. It’s suggested that this error could lead to Alzheimer’s, diabetes, and other genetic conditions.
SIRT1 is the sirtuin we know most about at this point. And as you read earlier, resveratrol targets SIRT1. It is the one substance we know that can activate it. Although, calorie restriction might also activate SIRT1.
The most recent findings with the SIRT1 gene provided breakthrough insights into how it is linked to aging. The research garnered Sinclair a spot on Time magazine’s list of the top 100 most influential people of the year in 2014.
Sinclair’s SIRT1 Breakthrough
For a long time, it was assumed that SIRT1 protected the function of the mitochondria. The mitochondria, as mentioned in Chapter 2, “Baby Science: How to Conceive a Tennis Star and Other Procreative Miracles,” is the cell’s energy turbine. When they aren’t functioning optimally the body’s motor functions slow down. This is why seniors move more slowly than 20-year-olds.
Why mitochondria break down over time is still unknown. If you think of the human body as a car, the process of natural wear and tear overtime is quite similar. Parts wear out. Humans happen to have the ability to regenerate themselves to a point (some cells die and are replaced) until aging catches up to them.
However, Sinclair’s team discovered that the SIRT1 breakdown does not directly cause mitochondrial breakdown. The process involves a chain of chemical events. SIRT1’s role is intermediary.
They discovered that SIRT1 is affected by a chemical called nicotinamide adenine dinucleotide (NAD) that determines whether SIRT1 functions at normal levels.
When SIRT1 is at normal levels it protects the cell from harmful intruders, like a chemical called hypoxia inducible transcription factor (HIF) that destroy the mitochondria. When HIF gets into the cell it causes disruption—much like a drunk at a party.
Think of it like this, SIRT1 is like a bouncer at the door of the nightclub. The SIRT1 bouncer keeps HIF-1 out of the club and protects the mitochondria inside. Think of NAD like a fitness coach in that the fitness coach (NAD) is the determining factor whether SIRT1 will be in shape enough to keep the HIF-1 out of the club.
Normal levels of NAD = Normal levels of SIRT1
When NAD malfunctions, SIRT1 can’t do its job to keep HIF-1 out and the intruder attacks the mitochondria, or at least barfs on his new shirt.
Sinclair’s team made this connection when they removed the SIRT1 gene from a group of mice, expecting the mice would show signs of aging and mitochondrial dysfunction. However, the researchers found the mitochondrial proteins remained at normal levels. When the research team investigated this further they discovered NAD. Research efforts are now focused on creating NAD-producing compounds that might one day help slow the aging process.
During preliminary trials, a NAD-producing compound was given to a group of mice for one week. When the research team examined the test rodents, their bodies had reverted back to a younger state. In human years, Sinclair said, “This would be like a 60-year-old converting to a 20-year-old in specific areas of the body.”
In 2013, another sirtuin breakthrough was made, this time by a team at the University of California at Berkeley. The research dealt with the SIRT3 gene. It was led by Danica Chen, UC Berkeley Assistant Professor of Nutritional Science and Toxicology.
At the time of the announcement, Chen said, “We already know that sirtuins regulate aging, but our study is the first one demonstrating that sirtuins can reverse aging-associated degeneration.” Chen’s lab reversed the aging process in a group of mice by manipulating the SIRT3 gene in a two-part process. The SIRT3 gene produces protein that helps blood cells cope with damage that automatically occurs when a cell produces energy.
SIRT6: Helpful, But Not
A team at the University of Chicago is actively researching the SIRT6 gene. Their most current research studies have provided insights into the role of its anti-aging properties and exciting prospects on treating cancer.
One study with transgenic mice showed that by overexpressing the SIRT6 gene in male mice, the mice lived 15 percent longer than normal.
In 2014, a second study with SIRT6 pointed to the gene as a cancer-causing agent. A research team at the university found a higher level of SIRT6 protein in sun-damaged skin cells compared to healthy skin.
To better understand the connection, they removed the SIRT6 from the skin cells of cancer-infected mice. Tumor production in those mice decreased.
Another focus of research in longevity science is the mTOR protein, or mechanistic target of rapamycin. Say that ten times fast!
The protein regulates cell growth in mammals. At the most basic level, the mTOR receives information from a number of growth-related biological processes. Then it makes a decision whether to start or stop the body’s growth response.
If this process malfunctions then diseases such as diabetes, obesity, depression, and various cancers might develop. Longevity research suggests that aging processes occur via similar cellular malfunctions. And those malfunctions occur when specific mTOR chemical pathways in the body become hyperactive.
Scientists first learned about mTOR while studying a molecule called rapamycin, back in the 1970s. It is a bacterial component that was first discovered in soil samples on Easter Island (a Polynesian Island in the southeastern Pacific Ocean. It’s the site of all those huge stone heads.)
The molecule has since been engineered into an FDA-approved drug. Rapamycin is an immunosuppressant, a drug that reduces activity in the immune system. It’s been used to treat cancer and prevent transplant rejection. It affects the mTOR protein specifically by binding to it and stop it from performing normal cell-regulation processes. Kind of like how an octopus on your face would stop you from driving.
Methuselah Mice and New MTOR Research
In 2013, Dr. Toren Finkel, Chief of Molecular Medicine from the National Heart, Lung, and Blood Institute, made a breakthrough discovery with the mTOR pathway. Finkel’s team bioengineered a group of mice that lived 20 percent longer than normal. Finkel’s mice lived to 28 to 31 months-old. Their average mice counterparts only lived 22 to 26 months.
The difference between Finkel’s “Methuselah Mice” and normal mice was a scaled-back mTOR gene. Finkel’s mice had a mTOR gene that had been cranked back to a quarter of its normal operating level using rapamycin.
Finkel’s mice had better balance and memory and also had improved organ function. However, they also had a greater loss of bone mass and more infection. It took them longer to age, but they weren’t healthy. This is due to an aging process that is not uniform. Aging occurs at various speeds in different parts of the body. When the study was published in 2013, Finkel told the Scientist magazine that he’s interested in learning how mTOR reduction affects aging cells. “Perhaps cells get rid of cellular garbage at a faster rate. That’s our best guess. But it’s a complete guess,” he said.
Insulin Signaling (Long Live the Worms)
When a species of worms lived to double their normal life span it piqued the interest of Tom Johnson and David Friedman, two scientists at the University of California at Irvine, who made a breakthrough discovery in 1988. The team identified two gene mutations (daf-2 and age-1) that contributed to the worm’s longevity.
More importantly, later research connected these genes to a pathway in both worms and humans called the insulin signaling pathway. Scientists are actively studying this pathway as a potential major player in longevity in humans.
The insulin signaling pathway is triggered by the hormone insulin when it’s released from the pancreas in the normal process of sugar metabolization that occurs in a healthy human. The release of insulin causes a number of chemical processes to be sent into motion that affect the body’s metabolism.
Insulin regulates the body’s ability to absorb sugar (glucose) that enters the bloodstream through food. During the process of digestion, insulin facilitates the body’s ability to absorb sugar. It allows sugar from the blood to be distributed to the skeletal muscles and fat tissue. That sugar is used for energy.
Restricting food intake by means such as calorie restriction affected the insulin signaling pathway of the worms that Johnson and Friedman were studying. When food was abundant the worms developed normally. When food was unavailable or the worms were overcrowded, they entered a long-lived larval state called dauer in which the aging process slowed down. Worms with this muted gene are also resistant to oxidative stress, along with environmental and bacterial pathogens.
The Curious Case of Laron’s Syndrome
An unusual group of people with a rare disease called Laron’s syndrome also connect the insulin signaling pathway to longevity. The disease impairs an important growth hormone affecting their ability to grow to normal adult height. Individuals with Laron’s syndrome are easily identified by their characteristic dwarfish appearance. However, their short stature is a bit of a trade-off if you consider the mutation they all have blocks life-threatening diseases such as diabetes and cancer.
Dr. Jaime Guevara-Aguirre, an Ecuadorean physician, has been studying Laron’s syndrome patients since the mid 1980s. He found the incidence of Laron’s syndrome was most common in remote villages in southern Ecuador, which were populated by descendants of conversos (Sephardic Jews from Spain and Portugal). In 1994, he learned that people with Laron’s syndrome were curiously immune to cancer and diabetes.
Dr. Valter D. Longo, of the University of Southern California, discovered that IGF-1, a hormone that makes normal children grow, was not present in Laron’s syndrome patients. He also learned that the process of IGF-1 creation in the body is directly associated to the GH receptor gene. To test his theory, he gave doses of IGF-1 to prepubescent Laron’s patients and found they grew to almost normal height.
Longo took a look at a laboratory roundworm that like humans, has what is known as the IGF-1 pathway. He found that knocking out a receptor known as DAF-2 (which basically makes IGF-1 work) allowed the worms to live longer.
And, like the DAF-2-less worms, Laron’s patients lack a normally functioning IGF-1 pathway. This is another possible reason for why they live longer.
In 2011, Longo and Guevara-Aguirre put their heads together. They took a genetically compounded serum from Laron’s patients and added it to human cells in a petri dish.
There were two key findings:
The cells were protected from genetic damage when the serum was added.
Any cells that were already damaged were destroyed. This mechanism is used by the body to stop the spread of cancerous cells.
When IGF-1 was added to the petri dish both the effects noted above were reversed. The scientists suggest that lowering the level of IGF-1 could be beneficial. A drug that does this could prolong life span.
AMPK, the Cellular Housekeeper
Let’s talk a bit about the adenosine monophosphate-activated protein kinase pathway. But, er, best we call it AMPK because otherwise this book is going to be much longer than it needs to be.
The AMPK pathway, similar to the mTOR pathway, is a regulator. It’s a master switch that handles metabolic change and protects cells by blocking unhealthy intruders.
Humans have the AMPK gene but in most people it’s turned off. However, it can be activated with drugs, diet, and exercise. When it gets turned on, it regulates the release of a molecule that allows cells to transfer energy. Simply put, it’s really good at cellular housekeeping and helps cells survive stress.
The good news is there is a drug on the market called Metformin that turns the AMPK pathway on. Metformin was invented in 1922 and has been in use since the 1950s to treat type 2 diabetes. The drug got some flak for a long list of side effects. But multiple studies proved it could decrease the incidence of cancer, heart disease, and even better, it can reverse aging.