Reduced Mitochondrial Fusion or Increased Fission Slows Aging in Flies

Researchers have demonstrated that shifting the balance between mitochondrial fusion and fission towards fission increases the life span of flies. The authors provide evidence to suggest that this is because greater fission enhances the operation of the quality control mechanisms of autophagy that clear away damaged mitochondria. This fits in with the wealth of studies that demonstrate modest increases in life span in a variety of species through enhanced autophagy, both of mitochondria and other damaged proteins and structures - better cellular repair and maintenance, in other words. Aging is a process of damage accumulation, and the more aggressively that cells clean up primary damage, the less of a chance that damage has to cause an accumulation of secondary and later effects.

Mitochondria are the evolved descendants of symbiotic bacteria, their presence an ancient and early development in the evolutionary tree of life. Every cell has a herd of hundreds of these structures, stripped of most of their original DNA, and integrated into the cell's quality control systems. Mitochondria divide like bacteria to make up their numbers, and when damaged are, in theory, destroyed by the processes of autophagy: tagged, wrapped, and dismantled by specialized machinery in the cell. Also like bacteria, mitochondria constantly split apart, fuse together, and promiscuously pass around copies of their molecular machinery.

Mitochondria are power plants, the last stage in the conversion of food into energy store molecules that a cell uses to power its operations. They are also generators of potentially damaging oxidative molecules, molecules that are also vital signals that trigger cell housekeeping and maintenance activities. Further, mitochondria play vital roles in a range of other portions of the cell life cycle, from replication to programmed cell death. All of this activity makes it hard to model or visualize in detail the progression of age-related damage in mitochondria, despite the overwhelming evidence for their importance in aging.

What little DNA mitochondria have left over is prone to damage, either because it has poor repair machinery in comparison to the cell nucleus, because it is right next door to the energy store creation mechanisms that produce damaging oxidative molecules as a byproduct, or because mitochondria replicate their DNA a lot more often than occurs for nuclear DNA. More dramatic forms of damage can block access to necessary proteins, turning off the most efficient energy store creation method, producing a mitochondrion that is both malfunctioning and more resistant to quality control efforts. Its descendants will very quickly take over the entire cell population, and the whole cell falls into a state of senescence or other dysfunction, exporting damaging molecules into the surrounding tissue. This is one of the root causes of aging. Researchers can see these cells after the fact, but observing and mapping the details of the process by which damaged mitochondria take over a cell in this way is yet to be achieved.

Fortunately, understanding exactly how this happens is not necessary in order to prevent it from happening. It doesn't matter how mitochondrial DNA is damaged or how damaged mitochondria overtake a cell if a supply missing proteins can be provided. Having a backup supply of the proteins encoded in mitochondria DNA bypasses all of the thorny questions and big unknowns, which is why it is the chosen strategy for the SENS rejuvenation research programs. The specific implementation involves allotopic expression, a gene therapy to place a mitochondrial gene into the cell nucleus, suitably adjusted such that the resulting protein is shipped back to mitochondria to be used. This has been demonstrated for three of the thirteen genes in recent years, one of which is the center of a commercial effort to repair inherited mitochondrial disease.

In this context, adjustments to mitochondrial dynamics of the sort demonstrated here look a lot like the quest for ways to mimic the response to exercise, the response to calorie restriction, or other favorable altered metabolic states. It is a shift of proportions and relative effectiveness of mechanisms, not a fix to the underlying problem. The potential upside of this sort of approach is typically not large - look at the survival curves in the paper here. This is noteworthy for producing those curves after a short treatment in middle age, rather than a life-long intervention, but it is still the case that it is a small effect in the grand scheme of things. Short-lived species such as flies have much greater plasticity of life span than long-lived species such as our own. In the few cases where effects can be compared fairly directly, adjustments of metabolic state that extend life significantly in worms, flies, and mice only add a few years at most to human life span.

Biologists slow aging, extend lifespan of fruit flies

In a study on middle-aged fruit flies, researchers substantially improved the animals' health while significantly slowing their aging. They believe the technique could eventually lead to a way to delay the onset of age-related diseases in humans. The approach focuses on mitochondria, the tiny power generators within cells that control the cells' growth and determine when they live and die. Mitochondria often become damaged with age, and as people grow older, those damaged mitochondria tend to accumulate in the brain, muscles and other organs. When cells can't eliminate the damaged mitochondria, those mitochondria can become toxic and contribute to a wide range of age-related diseases. Researchers found that as fruit flies reach middle age - about one month into their two-month lifespan - their mitochondria change from their original small, round shape. "We think the fact that the mitochondria become larger and elongated impairs the cell's ability to clear the damaged mitochondria. And our research suggests dysfunctional mitochondria accumulate with age, rather than being discarded."

The scientists removed the damaged mitochondria by breaking up enlarged mitochondria into smaller pieces - and that when they did, the flies became more active and more energetic and had more endurance. Following the treatment, female flies lived 20 percent longer than their typical lifespan, while males lived 12 percent longer, on average. The research highlights the importance of a protein called Drp1 in aging. At least in flies and mice, levels of Drp1 decline with age. To break apart the flies' mitochondria, researchers increased their levels of Drp1. This enabled the flies to discard the smaller, damaged mitochondria, leaving only healthy mitochondria. Drp1 levels were increased for one week starting when the flies were 30 days old.

Researchers further showed that the autophagy-related gene Atg1 also plays an essential role in turning back the clock on cellular aging. They did this by "turning off" the gene, rendering the flies' cells unable to eliminate the damaged mitochondria via autophagy. This proved that Atg1 is required to reap the procedure's anti-aging effects: While Drp1 breaks up enlarged mitochondria, the Atg1 gene is needed to dispose of the damaged ones. "We actually delayed age-related health decline. And seven days of intervention was sufficient to prolong their lives and enhance their health." One specific health problem the treatment addressed was the onset of leaky intestines, which previous research found commonly occurs about a week before fruit flies die. Subsequent research in other laboratories has determined that an increase in intestines' permeability is a hallmark of aging in worms, mice and monkeys. In this study, the condition was delayed after flies were given more Drp1.

In another part of the experiment, also involving middle-aged fruit flies, the scientists turned off a protein called Mfn that enables mitochondria to fuse together into larger pieces. Doing so also extended the flies' lives and improved their health. "You can either break up the mitochondria with Drp1 or prevent them from fusing by inactivating Mfn. Both have the same effect: making the mitochondria smaller and extending lifespan."

Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster

Mitochondrial dysfunction is a key hallmark of aging and has been linked to numerous age-onset pathologies. Therefore, identifying interventions that could improve mitochondrial homeostasis when targeted to aged animals would be highly desirable toward the goal of prolonging healthspan. A growing body of data support the idea that autophagy has an important anti-aging role. However, the relevant autophagic cargo in the context of aging remains elusive. Mitochondrial autophagy (mitophagy) is a type of cargo-specific autophagy, which mediates the removal of dysfunctional mitochondria. Recent studies in mammals, including humans, have reported an age-related decline in mitophagy. Moreover, impairment of mitophagy recapitulates the age-related accumulation of mitochondria in Caenorhabditis elegans. These findings suggest that the mitophagy pathway may represent a therapeutic target to counteract aging. However, a major unanswered question remains: why does mitophagy decline in aged animals?

Mitochondrial dynamics (fission and fusion) and mitophagy are closely related. Mitofusin (Mfn) proteins mediate fusion of the mitochondrial outer membrane, while mitochondrial fission, conversely, requires Dynamin-related protein 1 (Drp1). Several studies indicate that an important event preceding mitophagy is the Parkin-mediated turnover of Mfn leading to a shift in the balance of mitochondrial dynamics toward decreased fusion/increased fission. In yeast, the mitochondrial fission protein, Dnm1, homologous to Drp1, is required for certain forms of mitophagy. Together, these findings support the model that mitochondrial fission can promote the segregation of damaged mitochondria and facilitate their clearance by mitophagy. Critically, however, the interplay between mitochondrial dynamics and mitophagy during aging remains poorly understood, and the question of whether an increase in mitochondrial fission alone is sufficient to prolong lifespan and/or improve mitochondrial function in an aged animal has not been addressed.

Here, we show that inducing Drp1-mediated mitochondrial fission, in midlife, increases lifespan and improves multiple markers of health in aged Drosophila. Remarkably, we show that a transient induction of Drp1, for 7 days, in midlife is sufficient to prolong lifespan. Studying aging flight muscle, we find that a midlife shift toward a more elongated, less circular mitochondrial morphology is linked to the accumulation of dysfunctional mitochondria. Short-term, midlife Drp1 induction restores mitochondrial morphology to a youthful state, improves mitochondrial respiratory function and reduces mitochondrial reactive oxygen species (ROS) levels. Importantly, midlife Drp1 induction facilitates mitophagy and improves proteostasis in aged flies. Finally, we show that disruption of Atg1, a core autophagy gene, inhibits the anti-aging, prolongevity effects of midlife Drp1 induction. Our findings indicate that transient, midlife interventions that promote mitochondrial fission could delay the onset of frailty and mortality in aging mammals.

Comments

It's curious that in the nature paper the authors don't seem to be aware of the concept that mitochondrial gene deletions are causing the mitochondrial enlargement.

Posted by: Jim at September 7th, 2017 3:53 AM

@Jim: the enlargement and a number of other changes are too ubiquitous to be just problem deletions, as they happen in a minority of cells. There is a general mitochondrial malaise in older tissues. I think it probably in the class of unhelpful reactions to signaling, damage, changing protein levels.

Posted by: Reason at September 7th, 2017 6:59 AM

@jim What is the mechanism for deletionscausing enlargement?

Deletions are fairly predictable and can be rescued easily by mitotransplantation actually, no need for allotopic meddling. For example, in the heart ( https://www.researchgate.net/publication/310431730_Myocardial_Rescue_with_Autologous_Mitochondrial_Transplantation_in_a_Porcine_Model_of_IschemiaReperfusion ) transient ischemia quickly takes out a 7.3 kb chunk of mtDNA that includes 11 proteins. The breakpoints occur in the ATP synthase eight and cytochrome b genes near direct repeat sequences and other hotspots of mutation.

There were actually three significant papers yesterday addressing different aspects of mitodynamicsand dynamin related peptide (DRP). The presented this week at the mito furm in San Diego was interesting because the authors seemed to think that because they found that perturbed DRP resulted in failure of sperm mitos to properly form fusion networks after penetrating the egg, and that this explained loss of heteroplasmy and proper insurance of uniparental inheritance in the germline, that the Sharpley 2012idea that heteroplasmy = bad is upheld.

I talked to author David Chan last night and although something unique and possibly detrimental may happen in sperm to mitos, he still cites hetroplasmy.I think hetroplasmy, done properly, can be a wonderful thing actually, as we shall see.

Chan, David C. via caltech.onmicrosoft.com
Attachments5:26 PM (14 hours ago)

to me
Hi John,

Much of what I discussed has been published in the enclosed paper.

http://authors.library.caltech.edu/72195/3/e17896-download.pdf

I do think heteroplasmy is detrimental. Work from Doug Wallace's lab showed that heteroplasmy causes behavioral abnormalities in mice. I don't think the heteroplasmy per se is detected. The sperm mitochondria are different from the ones in the egg. Perhaps during the process of fertilization, they get damaged and become unable to fuse.

Posted by: john hewitt at September 7th, 2017 7:00 AM

"DNA DAMAGE DRIVES AGING VIA SUPPRESSION OF THE MITOCHONDRIAL UNFOLDED PROTEIN RESPONSE AND DAF -
16/FOXO3A ACTIVITY"

"Mitochondrial Function and Transcriptional Regulation during Denervation- Induced Skeletal Muscle Atrophy"

"EFFECT OF AGE ON SKELETAL MUSCLE MITOCHONDRIAL FUNCTION: INSIGHT FROM NEAR-INFRARED PECTROSCOPY"

All of these point to a secondary if not tertiary role of mitochondria in aging.

I think it's a good time to start thinking of a hierarchical model of aging from the point of view of intervention. Since advocates would need to work piecemeal as long as aging is not considered a treatable indication in itself, it's better to focus on the most immediate causes of dysfunction.

If we take the these free papers - the first one is self explanatory. The accumulation of somatic nDNA damage leads to a deregulation of mitochondrial function.
Although recent research points out that the soma has a significantly higher mutation rate than the germline (about 2.5 times higher) which leads to the implication DNA damage as a process MIGHT BE modifiable:
https://www.nature.com/articles/ncomms15183
I wouldn't hold my breath on that front for any near future breakthroughs and instead I'd rather see more focus on circumventing the problem by inducing a higher cellular turn over (safely if at all possible) and providing "fresh" cells. With this finding it seems freezing sperm makes more sense than freezing stem cells at least when it comes to DNA quality, something companies like Forever Labs should consider if they are at all serious about their claims.

In the second paper the neural niche which has a slow turn over to begin with and is further impaired in aging leads to a deregulation of the organ as a whole. Denervation should be modifiable with the right stem cell therapy. As long as you have a source of quality stem cells. Again the short term human prospects seem to lay in companies like Forever Labs and nuclear transfer technologies which will be expensive, "unethical" and in the long run unsustainable.

In the third we have an observation there are less mitochondria in old muscle in general, which might have something to do with the maintenance of the muscle itself, or might be caused by impaired mitophagy, or it might be caused by one of the previous two items. Or a combination.

A good collection of synopses anyway. Thanks for posting that one.

Posted by: Anonymoose at September 7th, 2017 8:40 AM

@anonmight youputthelinksto these interesting papers,my searchenginedoesn;tgive them immediately.

denervation atrophy likelyoccurs the sameas it does in hair follicles, otherwise regenerating tadpoles and salamander limbs, or anything else, namely, the nerves supply the mitos to control fate.

for you caloric restriction fiends, I just wrote andpubbed a little something a few minutes ago, featuring Fight Aging
https://medicalxpress.com/news/2017-09-caloric-restriction-anti-aging.html

Posted by: john hewitt at September 7th, 2017 9:07 AM

If you think about it, it is obvious that fission of mitochondria will result in a healthier mito population: fission makes the smallest possible into units, and if any have damaged DNA this will show up as a loss of membrane potential and tag them for autophagy. The remaining pop can then undergo mitogenesis leaving you better off than before. On the other hand big fused mitos will be more efficient at producing ATP but hide DNA damage. Any aging process that causes the body to favour fusion over fission will contribute to mitochondrial dysfunction in the long run.

Posted by: Mark at September 8th, 2017 4:28 AM

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