The Mystery of Aging, Solved at Last!

How many headlines have you seen that purport to reveal THE secret of aging?  Just in the last few weeks,  there have been several fundamental, earthshaking, paradigm-shifting, game-changing, disruptive discoveries–and they were very different one from another.

Why do these headlines keep popping up?  Is there truth in any of them?  …and, most interesting to me, What is it that they are all missing?

I’m a culprit in this game, too.  My publisher wants to call my forthcoming book Cracking the Aging Code.

I’m going to cover seven of these news releases below; I trust you’ll let me know if you want to hear more about any of them in particular.

Delay of Aging by Remote Control

“UCLA biologists have identified a gene that can slow the aging process throughout the entire body when activated remotely in key organ systems.”  [Science Daily from last fall]

AMP Kinase is a key chemical workhouse for energy production and regulation.  In this study, the AMPK gene in fruit flies was found to be a signal that controls autophagy throughout the body.  (Background: Autophagy is recycling at the cellular level.  It declines through the life span, with the result that molecular gunk accumulates and production of properly-formed proteins declines.)

Life span and health span of the flies were increased when the gene for AMPK was activated in the nervous system, and independently in the digestive system.

Role of Mitochondrial Damage vs Epigenetics

Jun-ichi Hayashi of Tsukuba University was an early enthusiast of the mitochondrial free radical theory of aging, who became convinced by his own lab results that the theory doesn’t work.

Background: Mitochondria are thousands of organelles inside a cell that burn sugar for electrochemical energy that the cell can use.  They have their own DNA and their own reproductive cycles within a cell.  They generate reactive oxygen species (ROS) as a byproduct, and it was an attractive theory to attribute aging to damage and mutations they suffer because they are at ground zero for high concentrations of ROS.

Over the last two decades, we have learned that mitochondria do indeed play a central role in aging, but the story is not about simple damage.  In his latest paper [research article, Science Daily report], researchers from Hayashi’s lab show that there is no difference in the amount of DNA damage in mitochondria from cells of young people and from old people.  Why then do mitochondria perform less well, and provide less energy in older people?  They go on to propose that it is the epigenetic programming (in the cell nucleus, not the mitochondria) that makes the difference, and they identified two genes (GCAT and SHMT2)  that may be all that is needed to restore youthful function to the mitochondria.  These genes control production of glycine, the simplest of the 20 amino acids that are common protein constitutents.  Simply feeding the cells with glycine also improved mitochondrial function.  (You can buy glycine tablets as a supplement, but the body already has a lot, so it’s a good guess you would need a lot of it to make a difference.  Food sources rich in glycine include gelatin, shrimp, spirulina, and raw ostrich meat.)

Simple Flip of a Genetic Switch

Johnathan Labbadia at Northwestern University has discovered an epigenetic switch, a set of genes that is turned on that begins the aging process in lab worms [Research article from the Morimoto lab, Science Daily summary].  Worms begin aging at the tender age of 3 days, just a few hours after adulthood, with a switch that represses Heat Shock Protein.  HSP is not jus for heat, but a high-level signal that invokes a set of responses that create resiliency in response to stress of many kinds.  In worms and in other animals, stress resistance is closely associated with longevity, and HSP is associated with longer life span in worms [ref].

Scientists who see aging as a purposeful, programmed event, myself included, look to mechanisms of epigenetic control, as we are hopeful that signaling can be modified to avert aging.  But traditional evolutionay biolgy denies that there can be such direct control of aging.  According to theory, such switches could only be flipped if flipping them increased reproduction in a way that more than offsets the loss of reproductive opportunity from aging.  In keeping with the standard theories, Labbadia and Morimoto, looked for a connection to reproduction in the epigenetic switch they discovered.  They found one, but–undermining the theory–they found that the benefits for reproduction and the costs in the form of aging could be easily separated.

“In one experiment, the researchers blocked the germline from sending the signal to turn off cellular quality control. They found the somatic tissues remained robust and stress resistant in the adult animals.”

Why doesn’t the worm do this, and get the best of both?  Must be some kind of mistake, the Northwestern team asserts.  “Dysregulation” has become a favorite word, though many have enough integrity and insight to be scratching their heads, wondering why there should be so much “dysregulation” involved in aging, when we rarely find anything else about the metabolism that is consistently dysregulated.

Older Blood Vessels are Better Protected against Oxidative Stress

This press release from University of Missouri descirbe evidence that cells of the arterial lining (epithelium) are more resistant to oxidative damage when they are older.  Research from the lab of Steven Segal used hydrogen peroxide (H2O2) as a stressor.  Peroxide is also known to be a multi-purpose signal molecule that can induce cell suicide (apotosis) in high concentrations, and can induce protective anti-aging response at lower levels [ref,ref].

The article is framed within an old and discredited view of that regards aging as a simple result of oxidative damage [ref].

“Although the causes of many age-related diseases remain unknown, oxidative stress is thought to be the main culprit. Oxidative stress has been linked to cardiovascular and neurodegenerative diseases including diabetes, hypertension and age-related cancers.”

It should no longer surprise us that anti-oxidants are not anti-aging [ref], or that pro-oxidants can be anti-aging [ref], or that aging is an active process controlled by central signals, not a passive process of damage [ref].

Getting to the Bottom of Aging

This article claims to find the root of aging at the cellular level.  In particular, it is in the endoplastic reticulum [background in a Kahn video]. The ER is a transport network inside the cell that directs each protein molecule to a targeted location.  It does more than this–it finishes and folds the protein after it is manufactured.  The new study finds differences between the ER of old and young cells, studied in lab worms and in cultured human cells.  [Here is a Science Daily summary.]  Proteins tend to be misformed and misfolded by the ER of old cells..

In direct contrast to the article just above on blood vessels (“oxidative stress is thought to be the main culprit” ), the claim here is that there is not enough oxidation in the ER of old cells.  It is the reduced state of the ER that is responsible for misfolding of proteins.

Diverging Paths from Parabiosis Experiments:  GDF11 and TGF-β

In the early 2000s, Irina Conboy and Amy Wagers were grad students in Tom Rando’s Stanford University lab, studying parabiosis in mice.  They learned that tissues in an old mouse could be rejuvenated by exchanging blood plasma with a young mouse.

Blood plasma is the liquid, containing dissolved signal molecules but no whole blood cells, no stem cells.  The implication was that the old tissues could receive instructions from other parts of the body (an epigenetic clock?) causing them to get older or to revert to a younger state.

Following up on this work: Now Irina and her husband Mike Conboy have a lab at UC Berkeley, where they are focusing on TGF-β as one of the signals that causes aging.  They are experimenting with a drug that blocks TGF-β receptor, and found that it has rejuvenating effects both on muscle and brain cells [press release, research article].  The implication is that excessive TGF-β in the blood is a source of aging.

Wagers is at the Harvard Stem Cell Center, where her biggest trophie so far is the discovery that GDF11 has rejuvenating effects in muscle and nerve cells.  The implication is that there is not enough GDF11 in the blood in the blood of older mammals, and this is a source of aging.

The irony is that GDF11 is a form of TGF-β.  The findings of Wagers and Conboy have diverged to the point where they have focused on the same signal as pro-aging (Conboy) and anti-aging (Wagers).

I don’t have the expertise to take sides in this disagreement, but others have noted that Wagers’s claim seems counter-intuitive. Doubts were expressed about Wagers’s findings by researchers at Novartis (a Cambridge, MA pharmaceutical lab), where David Glass claims he has been unable to duplicate Wagers’s work, and that in his experiments with mice, GDF11 seems to decline with age.

Wikipedia says, “GDF11 is a myostatin-homologous protein that acts as an inhibitor of nerve tissue growth. GDF11 has been shown to suppress neurogenesis through a pathway similar to that of myostatin.” [emphasis added].  Myostatin is an inhibitor of muscle growth whose structure is 90% homologous to GDF11.

Images of cells in the brain’s hippocampus show that the growth factor TGF-beta1 (stained red) is barely present in young tissue but ubiquitous in old tissue, where it suppresses stem cell regeneration and contributes to aging.

“The challenge ahead is to carefully retune the various signaling pathways in the stem cell environment, using a small number of chemicals, so that we end up recalibrating the environment to be youth-like,” Conboy said. “Dosage is going to be the key to rejuvenating the stem cell environment.”