Fight Aging! Newsletter, January 27th 2020

A lengthy-named gene called Elongation of Very Long Chain Fatty Acids Protein 2 or ELOVL2 is an established biomarker of age. Researchers found that an age-related decrease in ELOVL2 gene expression was associated with increased DNA methylation of its promoter. Methylation is a simple biochemical process in which groups of carbon and hydrogen atoms are transferred from one substance to another. In the case of DNA, methylation of regulatory regions negatively impacts expression of the gene. When researchers reversed hypermethylation in vivo, they boosted ELOVL2 expression and rescued age-related decline in visual function in mice.

ELOVL2 is involved in production of long-chain omega-3 and omega-6 polyunsaturated fatty acids, which are used in several crucial biological functions, such as energy production, inflammation response, and maintenance of cell membrane integrity. The gene is found in humans as well as mice. In particular, ELOVL2 regulates levels of docosahexaenoic acid or DHA, a polyunsaturated omega-3 fatty acid abundantly found in the brain and retina. DHA is associated with a number of beneficial effects. Notably, its presence in photoreceptors in eyes promotes healthy retinal function, protects against damage from bright light or oxidative stress and has been linked to improving a variety of vision conditions, from age-related macular (AMD) degeneration to diabetic eye disease and dry eyes.

Methylation of the regulatory region of the elongation of very-long-chain fatty acids-like 2 (ELOVL2) gene, an enzyme involved in elongation of long-chain polyunsaturated fatty acids, is one of the most robust biomarkers of human age, but the critical question of whether ELOVL2 plays a functional role in molecular aging has not been resolved. Here, we report that Elovl2 regulates age-associated functional and anatomical aging in vivo, focusing on mouse retina, with direct relevance to age-related eye diseases.

We show that an age-related decrease in Elovl2 expression is associated with increased DNA methylation of its promoter. Reversal of Elovl2 promoter hypermethylation in vivo through intravitreal injection of 5-Aza-2'-deoxycytidine (5-Aza-dc) leads to increased Elovl2 expression and rescue of age-related decline in visual function. Mice carrying a point mutation C234W that disrupts Elovl2-specific enzymatic activity show electrophysiological characteristics of premature visual decline, as well as early appearance of autofluorescent deposits, well-established markers of aging in the mouse retina. Finally, we find deposits underneath the retinal pigment epithelium in Elovl2 mutant mice, containing components found in human drusen, a pathologic hallmark of age related macular degeneration.

These findings indicate that ELOVL2 activity regulates aging in mouse retina, provide a molecular link between polyunsaturated fatty acids elongation and visual function, and suggest novel therapeutic strategies for the treatment of age-related eye diseases.

Researchers profiled a group of 43 healthy men and women between the ages of 34 and 68, taking extensive measurements of their molecular biology at least five times over two years. The researchers determined that people generally age along certain biological pathways in the body: metabolic, immune, hepatic (liver) and nephrotic (kidney). People who are metabolic agers, for example, might be at a higher risk for diabetes or show signs of elevated hemoglobin A1c, a measure of blood-sugar levels, as they grow older. People with an immune ageotype, on the other hand, might generate higher levels of inflammatory markers or be more prone to immune-related diseases as they age. But the ageotypes are not mutually exclusive, and a metabolic ager could also be an immune ager, for example.

Just because an individual falls into one or more of the four ageotypes - metabolic, immune, hepatic and nephrotic - doesn't mean that they're not also aging along the other biological pathways. The ageotype signifies the pathways in which increases in aging biomarkers are most pronounced. Perhaps most exciting - and surprising - is that not everyone in the study showed an increase in ageotype markers over time. In some people, their markers decreased, at least for a short period, when they changed their behavior. They still aged, but the overall rate at which they did so declined, and in some cases aging markers decreased. In fact, the team saw this phenomenon occur in a handful of important clinical molecules, including hemoglobin A1c and creatine, a marker for kidney function, among a small subset of participants.

In that subset, there were individuals who made lifestyle changes to slow their aging rate. Among those who exhibited decreased levels of hemoglobin A1c, many had lost weight, and one made dietary changes. Some who saw a decrease in creatine, indicating improved kidney function, were taking statins. In other cases, exactly why rates of aging markers waned was unclear. For some people, there were no obvious behavioral changes, yet the team still saw a decreased rate of aging along their ageotype pathways. There was also a handful of people that maintained a slower-than-average aging rate throughout the entire study. How or why is still a mystery.

The molecular changes that occur with aging are not well understood. Here, we performed longitudinal and deep multiomics profiling of 106 healthy individuals from 29 to 75 years of age and examined how different types of 'omic' measurements, including transcripts, proteins, metabolites, cytokines, microbes, and clinical laboratory values, correlate with age. We identified both known and new markers that associated with age, as well as distinct molecular patterns of aging in insulin-resistant as compared to insulin-sensitive individuals. In a longitudinal setting, we identified personal aging markers whose levels changed over a short time frame of 2-3 years. Further, we defined different types of aging patterns in different individuals, termed 'ageotypes', on the basis of the types of molecular pathways that changed over time in a given individual. Ageotypes may provide a molecular assessment of personal aging, reflective of personal lifestyle and medical history, that may ultimately be useful in monitoring and intervening in the aging process.

Autophagy is an evolutionarily conserved bulk cellular degradation system that functions to breakdown and recycle a wide array of cytoplasmic components from lipids, proteins, and inclusion bodies, to whole organelles (e.g. mitochondria). Importantly a reduction in autophagic flux (the rate at which autophagosomes form and breakdown cellular contents) is associated with increasing age in mammals. Evidence from lower organisms suggests that autophagy inhibition can negate the positive-effects of regimens that extend lifespan, such as calorie restriction, rapamycin supplementation, and mutations in insulin signalling pathways.

In mice, the constitutive promotion of autophagy throughout lifetime has been shown to extend health- and life-span in mammalian models. These studies have provided hitherto missing evidence that autophagic flux can impact on mammalian longevity and supports the notion that the pharmacological promotion of autophagy may extend health-, and potentially life-span, in humans. However, whether a reduction in autophagy is sufficient to induce phenotypes associated with ageing, and whether these effects can be reversed by restoring autophagy has to date not been addressed. Considering that the therapeutic window for pharmacological intervention to counteract ageing, and age-related diseases, will be later in life (as opposed to from conception), after autophagic flux has declined, it is critical to understand how the temporal modulation (inhibition and restoration) of autophagy may impact on longevity and health.

To address these questions, we use two doxycycline (dox) inducible shRNA mouse models that target the essential autophagy gene Atg5 to demonstrate that autophagy inhibition in young adult mice is able to drive the development of ageing-like phenotypes and reduce longevity. Importantly we confirm that the restoration of autophagy is associated with a substantial restoration of health- and life-span, however this recovery is incomplete. Notably the degree of recovery is segmental, being dependent on both the tissue and metric analysed. A striking consequence of this incomplete restoration is that autophagy restored mice succumb to spontaneous tumour formation earlier and at an increased frequency than control mice, a phenotype not observed during autophagy inhibition alone. As such our studies indicate that despite the significant benefit, autophagy reactivation may also promote tumorigenesis in advanced ageing context.

Since the discovery of HIF-1α, several seminal works have identified the changes in HIF associated with age and the development of age-related disorders, including neurodegenerative diseases. Importantly, in 2009, researchers described HIF-1 as a longevity factor, demonstrating that HIF-1 stabilization is associated with a 30-50% increase in lifespan in nematodes. Several studies have shown that stabilization of HIF-1 increases longevity and healthspan through different pathways in Caenorhabditis elegans. These critical findings in worms yielded a new perspective on the study of HIF stabilization and lifespan among mammals. However, the stabilization of mammalian HIF-1α has been implicated in tumor growth and cancer development and may therefore be harmful. Consequently, a balance between the beneficial and detrimental effects of HIF is critical for homeostasis and depends on the involved components and their contribution to longevity.

Studies on skin, a tissue that is continuously exposed to intrinsic and extrinsic aging factors, have identified HIF-1α as a crucial determinant of skin homeostasis, especially in epidermal aging and wound healing. Results have reported that the loss of epidermal HIF-1α accelerates epidermal aging and affects re-epithelialization in humans and mice. Notably, significant elevations in both hypoxia-inducible transcription factors HIF-1α and HIF-1β gene expression have also been found in the gingival tissues of aged animals, even though these tissues were deemed clinically healthy. In a model of limb ischemia in mice, HIF-1 was found to mediate angiogenesis and, therefore, has been proposed to contribute to the pathological aging process.

HIF is not only a transcriptional factor that regulates tissue oxygenation (including angiogenesis and vascular remodeling) but also controls redox balance, inflammation, and glucose metabolism to eventually maintain cellular homeostasis. According to current knowledge, the age-dependent impairment of HIF-1α induction leads to diminished vascular responses to limb ischemia and less effective wound healing. Some evidence shows the functionally important expression of HIF-1α among ischemic limb mice. It has been demonstrated that the abundance of the HIF-1α protein is decreased in ischemic tissues from aged mice and has also been linked with the downregulation of genes encoding angiogenic growth factors. Another vital player of vascular aging, which is positively regulated by HIF-1, is vascular endothelial growth factor (VEGF), a central mediator of angiogenesis. During aging, there is a defect in HIF-1 activity, yielding VEGF expression reduction and leading to the impairment of angiogenesis in response to the ischemia model.

Recently, we found that HIF-1α is involved in p53, p16, cyclin D1, and lamin B1-mediated senescence in vascular endothelial cells (ECs). Moreover, senescent ECs failed to express HIF-1α, and the microvesicles released by these cells were unable to carry HIF-1α. In another study, HIF-1α was found to play a critical regulatory role in vascular inflammation of macrophages after an intimal injury, through limiting an excessive degree of vascular remodeling. The mechanism by which macrophage-derived HIF-1α mediated this effect is still unknown. Considering these findings, HIF-1α may represent a possible therapeutic target in vascular diseases, especially in vascular aging.

One promising therapeutic intervention to impede age-related functional decline is endurance exercise. Endurance training induces remodeling in muscle tissue that alters the metabolic health of the entire organism. Evidence from humans and model organisms strongly suggests that endurance exercise has substantially protective effects on various indices of healthspan. These changes are often thought to be at least partially mediated by exercise-induced upregulation of AMP-activated protein kinase (AMPK) and the insulin-AKT pathway.

Sestrins are small stress-inducible proteins that are found throughout the animal kingdom. Mammals express three Sestrins (Sesn1-3), while Drosophila and C. elegans express one Sestrin orthologue. Once induced, Sestrins coordinate metabolic homeostasis by regulating multiple signaling pathways. Through its intrinsic oxidoreductase activity and by regulating autophagy, Sestrin can function as an antioxidant to reduce oxidative damage in cells. Importantly, while Sestrins downregulate TORC1/S6K signaling, they strongly activate TORC2/AKT signaling.

Here, using Sestrin-deficient fly and mouse models, we show that Sestrins play a critical role in mediating chronic exercise adaptations and exercise benefits. Genetic ablation of Sestrins prevents organisms from acquiring metabolic benefits of exercise and improving their endurance through training. Conversely, Sestrin upregulation mimics both molecular and physiological effects of exercise, suggesting that it could be a major effector of exercise metabolism.

Researchers have found that by genetically switching off a receptor activated by blood proteins, named Protease Activated Receptor 1 (PAR1), the body switches on regeneration of myelin, a fatty substance that coats and protects nerves. "Myelin regeneration holds tremendous potential to improve function. We showed when we block the PAR1 receptor, neurological healing is much better and happens more quickly. In many cases, the nervous system does have a good capacity for innate repair. This sets the stage for development of new clinically relevant myelin regeneration strategies."

Myelin acts like a wire insulator that protects electrical signals sent through the nervous system. Demyelination, or injury to the myelin, slows electrical signals between brain cells, resulting in loss of sensory and motor function. Sometimes the damage is permanent. Demyelination is found in disorders such as MS, Alzheimer's disease, Huntington's disease, schizophrenia, and spinal cord injury. Thrombin is a protein in blood that aids in healing. However, too much thrombin triggers the PAR1 receptor found on the surface of cells, and this blocks myelin production. Oligodendrocyte progenitor cells capable of myelin regeneration are often found at sites of myelin injury, including demyelinating injuries in multiple sclerosis.

The research focused on two mouse models. One was an acute model of myelin injury and the other studied chronic demyelination, each modeling unique features of myelin loss present in MS, Alzheimer's disease, and other neurological disorders. Researchers genetically blocked PAR1 to block the action of excess thrombin. The research not only discovered a new molecular switch that turns on myelin regeneration, but also discovered a new interaction between the PAR1 receptor and a very powerful growth system called brain derived neurotropic factor (BDNF).

Significantly, the researchers found that a current FDA-approved drug, vorapaxar, that inhibits the PAR1 receptor also showed ability to improve myelin production in cells tested in the laboratory. "It is important to say that we have not and are not advocating that patients take this inhibitor at this time. We have not used the drug in animals yet, and it is not ready to put in patients for the purpose of myelin repair. Using cell culture systems, we are showing that this has the potential to improve myelin regeneration."

Researchers have found that after stroke, exosomes - nanosized biological suitcases packed with an assortment of cargo that cells swap, like proteins and fats - traveling in the blood get activated and sticky and start accumulating on the lining of blood vessels. Like a catastrophic freeway pileup, platelets, also tiny cells that enable our blood to clot after an injury, start adhering to the now-sticky exosomes, causing a buildup that can effectively form another clot, further obstruct blood flow to the brain and cause additional destruction.

One thing traveling exosomes typically aren't is sticky. Rather, much like our real suitcases, they have a smooth label that marks their intended destination. But when these external destination tags become inexplicably sticky following a stroke, not only do exosomes not reach their destination, they can worsen stroke outcome. In a bit of a perfect storm, the scientists have shown in both stroke models and human blood vessels that exosomes cruising through the blood then pick up RGD, the unique and normally sticky peptide sequence, arginine-glycine-aspartate, which is key to the pileup that can cause additional brain damage.

More typically, exosomes carry a negligible amount of RGD, a protein that's important in holding together the extracellular matrix that helps cells connect and form tissue. In the aftermath of a stroke, cells and the extracellular matrix both get damaged, and sticky RGD is effectively set free. Platelets normally aren't exposed to RGD, which should mostly be sequestered in the extracellular matrix, so they become angry, activated and also sticky in response.

Another piece of this sticky situation is that a receptor called αvβ3. Avβ3 also is found on the lining of blood vessels and naturally binds to sticky RGD as part of its role with the extracellular matrix. The new stroke study shows the RGD carrying exosomes also target these receptors. In fact, when scientists gave antibodies to αvβ3, the binding to the blood vessel lining was blocked. A bottom line of the new work is that RGD sequences are a key contributor to the secondary damage from stroke.

Researchers have presented brain imaging data for a new stroke treatment that supported full recovery in swine, modeled with the same pattern of neurodegeneration as seen in humans with severe stroke. The researchers report the first observational evidence during a midline shift - when the brain is being pushed to one side - to suggest that a minimally invasive and non-operative exosome treatment can now influence the repair and damage that follow a severe stroke.

Exosomes are considered to be powerful mediators of long-distance cell-to-cell communication that can change the behavior of tumor and neighboring cells. The results of the study echo findings from other recent studies using exosome technology. Many patients who suffer stroke exhibit a shift of the brain past its center line-the valley between the left and right part of the brain. Lesions or tumors will induce pressure or inflammation in the brain, causing what typically appears as a straight line to shift. "Based on results of the exosome treatment in swine, it doesn't look like lesion volume or the effects of a midline shift matter nearly as much as one would think. This suggests that, even in some extremely severe cases caused by stroke, you're still going to recover just as well."

Trauma from an acute stroke can happen quickly and can cause irreversible damage almost immediately. Data from the team's research showed that non-treated brain cells near the site of the stroke injury quickly starved from lack of oxygen and died - triggering a lethal action of damage signals throughout the brain network and potentially compromising millions of healthy cells. However, in brain areas treated with exosomes that were taken directly from cold storage and administered intravenously, these cells were able to penetrate the brain and interrupt the process of cell death.

T-cell therapies for cancer - where immune cells are removed, modified and returned to the patient's blood to seek and destroy cancer cells - are the latest paradigm in cancer treatments. The most widely-used therapy, known as CAR-T, is personalised to each patient but targets only a few types of cancers and has not been successful for solid tumours, which make up the vast majority of cancers. Researchers have now discovered T-cells equipped with a new type of T-cell receptor (TCR) which recognises and kills most human cancer types, while ignoring healthy cells. This TCR recognises a molecule present on the surface of a wide range of cancer cells as well as in many of the body's normal cells but, remarkably, is able to distinguish between healthy cells and cancerous ones, killing only the latter.

Conventional T-cells scan the surface of other cells to find anomalies and eliminate cancerous cells - which express abnormal proteins - but ignore cells that contain only "normal" proteins. The scanning system recognises small parts of cellular proteins that are bound to cell-surface molecules called human leukocyte antigen (HLA), allowing killer T-cells to see what's occurring inside cells by scanning their surface. HLA varies widely between individuals, which has previously prevented scientists from creating a single T-cell-based treatment that targets most cancers in all people. The new study describes a unique TCR that can recognise many types of cancer via a single HLA-like molecule called MR1. Unlike HLA, MR1 does not vary in the human population - meaning it is a hugely attractive new target for immunotherapies.

T-cells equipped with the new TCR were shown, in the lab, to kill lung, skin, blood, colon, breast, bone, prostate, ovarian, kidney and cervical cancer cells, while ignoring healthy cells. To test the therapeutic potential of these cells in vivo, the researchers injected T-cells able to recognise MR1 into mice bearing human cancer and with a human immune system. This showed "encouraging" cancer-clearing results which the researchers said was comparable to CAR-T therapy in a similar animal model.

Three new studies add to growing evidence that damaged blood vessels wreak havoc on the brain, but not by exacerbating amyloid-β (Aβ) deposition. One found no correlation between intracerebral atherosclerosis and overall amyloid plaque burden in cognitively normal older adults. Another reported that midlife atherosclerosis in the carotid artery upped future risk of vascular dementia, but not Alzheimer's disease (AD). A third found that white-matter hyperintensities - a proxy for damage to small vessels in the brain - had no bearing on future changes in AD biomarkers.

On their own, faulty blood vessels in the brain can cause cognitive impairment and dementia. Blood-vessel disease is also thought to contribute to the clinical symptoms of AD, since people with Alzheimer's often have vascular pathology along with amyloid plaques and neurofibrillary tangles. Regardless of whether vascular dysfunction has an additive or synergistic relationship with AD pathology in influencing cognitive decline, the crucial point is that good blood vessel health benefits the brain. A person's vascular risk is highly modifiable by way of lifestyle choices or, if need be, medication.

Immunosenescence is a major cause of increased incidence and severity of viral infections in the elderly, and contributes to impaired immunogenicity and efficacy of vaccines. Understanding the biological basis for age-associated alterations in viral immunity and vaccine immunogenicity is a challenge with substantial clinical importance. Subsequently, the use of systems biology approaches in combination with computational model systems will be crucial to understand the complexity of age-associated changes in the immune system by identifying molecular networks that orchestrate immunity to vaccinations in humans and potentially define correlates of protection.

Given the plastic nature of aging and rapidly growing field of systems biology, molecular profiling of the aging-related changes is increasingly being examined at a single cell level by high-throughput omics technologies, including genomics, metagenomics, transcriptomics, and metabolomics. Specially, aging of the immune cells is affected by changes in homeostasis via cytokine levels, and by modifications in the metabolic pathways. Caloric restrictions (CR) affected a marked improvement in the maintenance and/or production of naïve T cells and the consequent preservation of TCR repertoire diversity. Furthermore, CR also improved T cell function and reduced production of inflammatory cytokines by memory T cells, suggesting that CR can delay T cell senescence and potentially contribute to extended lifespan by reducing susceptibility to infectious diseases.

A key area for future exploration in the immunosenescence field is the role of the secondary lymphoid organs as a critical partner in the development and function of the aging human immune system. It will be important to analyze age-related changes in secondary lymphoid organs, lymph nodes and spleen, given the aging-associated decrease in the size of lymph nodes. Lymph nodes not only serve as the key initiating region of the immune response, but they also play an important role in maintaining naive lymphocytes.

Next, investigation of how extracellular vesicles (EVs) are linked to aging could be a promising area of interest. EVs are membrane-bound vesicles released by multiple cell types that include immune cells. Evidence from cellular models suggests that exosomes released by macrophages from older are more pro-inflammatory than those released by macrophage from younger. In particular, mRNA levels of IL-6 and IL-12, but not TNF-α, in macrophage-derived exosomes were significantly higher in serums of older subjects. Given that EVs play an important role in immune cell network and cellular senescence, the profiles of secretome and the function of senescent immune cells will soon be revealed as the EV research field progresses.

Increasing evidence points to a provocative role of sustained, sub-clinical inflammation, often termed "inflammaging," in the development of these chronic disorders. In support of this notion, chronologically aged humans (≥50 years) display elevated circulating levels of pro-inflammatory cytokines, particularly IL-6, IL-1β, and TNFα. Moreover, subjects with chronic cutaneous inflammatory diseases, such as psoriasis and eczematous dermatitis, also display an increased prevalence of aging-associated disorders, including atherosclerotic cardiovascular disease, obesity, and type 2 diabetes. Though anti-inflammatory regimens, such as inhibitors of IL-1βα and TNFα, as well as methotrexate, have been deployed in the management of these aging-associated disorders, the outcomes of treatments with these agents have been inconclusive.

While many chronologically aged humans merely display marked evidence of inflammation, they nonetheless display elevated circulating levels of cytokines, suggesting that one or more, as yet identified organs, could account for the aging-associated increase in circulating cytokines. It seems reasonable to postulate that the responsible organs must be large enough to sustain such an increase in circulating cytokines, even without noticeable inflammation. Although the musculoskeletal system is the largest organ in humans, most chronologically aged humans display no evidence of musculoskeletal inflammation.

Other relatively large organs to be considered include the skin, intestines, lungs, and liver. The skin weighs about 20 lbs (with an additional, variable contribution from subcutaneous adipose tissues), while the weights of the intestines, lungs, and liver represent ≈7.5, 5.0 and 3.3 lbs, respectively. Because of their relatively lesser size, inflammation of the lungs, intestines, and liver likely would not only need to be apparent, but also sustained if any of these organs could account for the increase in circulating levels of cytokines. Yet again, the majority of otherwise normal aged humans display few clinical signs or symptoms of inflammation in these organs. Hence, it seems unlikely that they could contribute substantially to "inflammaging" unless multiple organs simultaneously exhibit mild inflammation. Notably, the aged skin commonly exhibits signs and symptoms of inflammation, such as pruritus and senile xerosis.

Because of its relatively large size, we hypothesized that the skin could be an important contributor to the elevated levels of circulating cytokines in chronologically aged humans, despite the fact that it typically displays little evidence of inflammation. Not only its size, but also its unique anatomic site, serving as the interface between the body and external environment, supports our hypothesis. In this site, it is continuously exposed to external physical and chemical stressors, which themselves can provoke inflammation, even as other less-exposed organs remain quiescent. In addition, chronologically aged humans display alterations in several key epidermal functions, each of which can provoke low-grade, chronic inflammation in the skin.

While there is consensus that the immune system is intimately involved in Alzheimer's disease (AD), there is considerable debate over which aspects of inflammation are harmful and contribute to degeneration, and which are protective and may prevent cognitive decline. Furthermore, it has yet to be established which components of the immune system actively play a role in pathology and which are just a consequence of disease. Gliosis, or increased numbers of activated astrocytes and microglia are a hallmark feature of neuroinflammation. However, past descriptions of this phenomenon, namely just "reactive" or "increased gliosis" are vastly oversimplified. Recent evidence highlights altered glia-specific pathways in post-mortem AD tissue and in mouse models of AD, suggesting that glial responses are much more heterogeneous and complex than previously thought.

While neuroinflammation can promote efficient clearance of amyloid-β and neuronal debris it can also accelerate disease by causing neuronal and glial cell death. This inflammatory balance is highly orchestrated and understanding how to regulate these responses is key to developing effective therapeutics for AD. The initiation of an immunological reaction can be beneficial and critical, allowing for a burst of glial activity to protect and repair the site of damage, and to clear toxic species or dysfunctional synapses. For example, in response to adverse conditions, microglia will undergo morphological changes, accompanied by the release of a storm of molecular mediators that increases clearances of amyloid-β. Furthermore, various types of non-neuronal cells are recruited to the site to assist in repairing the damage and consolidating excessive inflammation. These reparative processes are beneficial, yet may also have harmful consequences such as sustained cytokine release which can become toxic to neuronal cells. Therefore, understanding the specific cellular roles and inflammatory reactions in AD is of vital importance.

Mitochondrial health is vital for cellular and organismal homeostasis, and mitochondrial defects have long been linked to the pathogenesis of neurodegenerative diseases such as Alzheimer's, Parkinson's, ALS, Huntington's, and others. However, it is still unclear whether cellular mechanisms required for the maintenance of mitochondrial integrity and function are deficient in these diseases, thus exacerbating mitochondrial pathology. The quality control of mitochondria involves multiple levels of strategies to protect against mitochondrial damage and maintain a healthy mitochondrial population within cells. In neurons, mitophagy serves as a major pathway of the quality control mechanisms for the removal of aged and defective mitochondria through lysosomal proteolysis. The molecular and cellular mechanisms that govern mitophagy have been extensively studied in the past decade. However, mitophagy deficit has only been recognized recently as a key player involved in aging and neurodegeneration.

Given the fact that mitochondrial deficit is clearly linked to neuronal dysfunction and the exacerbation of disease defects, protection of mitochondrial function could be a practical strategy to promote neuroprotection and modify disease pathology. Mitochondrially targeted antioxidants have been proposed. In particular, the antioxidant MitoQ, a redox active ubiquinone targeted to mitochondria, has been examined and demonstrated to have positive effects in multiple models of aging and neurodegenerative disorders. Importantly, mitophagy could be another promising target for drug discovery strategy. Therefore, further detailed studies to elucidate mitophagy mechanisms not only advance our understanding of the mitochondrial phenotypes and disease pathogenesis, but also suggest potential therapeutic strategies to combat neurodegenerative diseases.