Hallmarks of aging Suggest an improvement to this article

Contents

  1. Mechanisms/biomarkers of aging
    1. Genomic instability
      1. Detecting genomic instability with gamma-H2AX
      2. Response to DNA damage
      3. Inhibition of histone deacetylases (HDACs) restores genomic stability
    2. Telomere attrition
    3. Epigenetic alterations
      1. DNA methylation
      2. Histone modification
    4. Loss of proteostasis
    5. Deregulated nutrient sensing
    6. Mitochondrial dysfunction
    7. Cellular senescence
    8. Stem cell exhaustion
    9. Altered intercellular communication
  2. Inflammaging
  3. Contributors to interindividual differences in the accumulation of hallmarks of aging
    1. Diet
    2. Exercise
    3. Temperature-induced biological stress
    4. Supplements and medications
    5. Other lifestyle factors
  4. Related topics and episodes
  5. Relevant publications
Hallmarks of aging episodes Hallmarks of aging news

Aging refers to the collective physiological, functional, and mental changes that accrue in a biological organism over time. The hallmarks of aging are observable biological patterns of dysfunction that occur with aging. Integral to the aging process is inflammaging, the chronic, low-grade inflammation that occurs with aging.[1] The mechanisms that drive inflammaging and the pathological conditions that arise because of it are bidirectional and involve multiple physiological processes and pathways, many of which directly or indirectly intersect with some of the hallmarks described below. (For more on this, see the "Inflammaging" section later in the article.)

Current research recognizes nine hallmarks of aging.[2]

  • Genomic instability, the increased tendency for DNA mutations (e.g., base deletions, additions, or substitutions) and other genetic changes (e.g., chromosome architecture) to occur over time.

  • Telomere attrition, the shortening of the protective caps on the end of DNA that happens as cells divide over time, leaving DNA more vulnerable to mutations.

  • Epigenetic alterations, non-sequential changes in DNA that accumulate over time and contribute to the loss of proteostasis.

  • Loss of proteostasis, the inability of cells to maintain the levels of proteins and enzymes needed for a cell to function correctly.

  • Deregulated nutrient sensing, the declining responsiveness of cells to changes in fuel availability in the body.

  • Mitochondrial dysfunction, impaired mitochondrial function that occurs over time as mitochondrial membranes and energy production become less efficient.

  • Cellular senescence, the process by which damaged cells terminate normal growth and reproduction cycles to prevent injured cells from proliferating.

  • Stem cell exhaustion, a phenomenon that occurs as progenitor cells reproduce to give rise to new specialized cells (e.g., skin, liver, cardiac, skeletal muscle cells) but can accelerate due to environmental exposures.

  • Altered intercellular communication, the diminished capability of cells of different tissue types (e.g., skin, liver, muscle) to communicate their status and behavior to each other.

Mechanisms/biomarkers of aging

"Accelerated biological aging drives many of the chronic diseases common to industrialized nations, such as cardiovascular disease, type 2 diabetes, cancer, and neurodegenerative diseases." Click To Tweet

The hallmarks mentioned above increase in severity over time for most living organisms, but the rate of declining function depends upon several genetic and environmental factors specific to each individual. Accelerated biological aging drives many of the chronic diseases common to industrialized nations, such as:[2]

  • Cardiovascular disease
  • Type 2 diabetes
  • Cancer
  • Neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease)

The following section elaborates on the mechanisms and biomarkers associated with the hallmarks of aging.

Genomic instability

"The principal drivers of genomic instability are defects in processes that modulate cell division." Click To Tweet

Genomic instability refers to an increased tendency for genetic alterations, such as mutations and chromosome rearrangements, to occur over time during cell division. It is a defining characteristic of aging. In humans, genomic instability is often associated with inherited diseases, predisposition to some cancers, and premature aging.

Defects in processes that modulate cell division, such as mutations in genes that participate in DNA repair, uncorrected errors during replication, or broken, missing, rearranged, or extra chromosomes, are the principal drivers of genomic instability.[3] Cellular checkpoints and DNA damage-response pathways help preserve genomic stability and cell-cycle progression, but these processes decline with aging.[4]

Detecting genomic instability with gamma-H2AX

There are five known histone proteins: H1, H2A, H2B, H3, and H4. Histone 2A has several variants, including H2AX, which plays essential roles in DNA repair, specifically non-homologous end joining, a pathway that repairs double-strand breaks. Damage to DNA via exposure to ionizing radiation, certain drugs, or cytotoxic agents induces phosphorylation of a specific amino acid on H2AX.[5]

Phosphorylated H2AX, known as gamma-H2AX, is a robust indicator of DNA damage. As such, it may serve as a prognostic marker for cancer and a biomarker for many age-related diseases.[6] [7]

Response to DNA damage

"Cellular DNA is subject to tens of thousands of injuries daily." Click To Tweet

Cellular DNA is subject to tens of thousands of daily injuries arising from endogenous sources, such as free radicals produced during normal metabolism, and exogenous sources, such as cytotoxic drugs, ionizing radiation, and cigarette smoke.[8] The DNA damage response pathway is a set of signaling pathways that cells use to maintain genomic integrity and repair damage after injury; however, the efficiency and activity of these pathways diminish with aging.

The first step in initiating DNA repair is recognizing the damage via injury-specific sensing molecules and subsequent recruitment of signal transducers, primarily enzymes called kinases. Then, various checkpoints and repair systems, including cell cycle regulators, nucleases, helicases, polymerases, and ligases, remove the damage, thus maintaining genomic integrity. Repair systems are injury-specific and include:[9]

  • Non-homologous end-joining and homologous recombination (repair double-strand breaks)
  • Single-strand break repair (repairs damaged DNA strands)
  • Mismatch repair (corrects errors that occur during replication)
  • Base excision repair (reverses oxidative base modifications)
  • Nucleotide excision repair (removes injuries that distort the helix)

Leaving these injuries unrepaired can lead to cell death and bodily disease.

Inhibition of histone deacetylases (HDACs) restores genomic stability

"Dietary compounds that inhibit HDAC activity, such as curcumin, resveratrol, and berberine, show promise as anti-aging therapies." Click To Tweet

HDACs are enzymes of particular interest to the field of aging research. They function as "global" transcriptional regulators, influencing gene expression via deacetylation of histone proteins (molecules that provide structural and functional support to DNA) and non-histone proteins, including a wide range of proteins that regulate gene transcription. HDACs also regulate the activity of critical physiological processes that maintain homeostasis and promote longevity, including cell-cycle regulation, cell growth and differentiation, DNA damage response, and apoptosis (a cellular self-destruct mechanism).[10]

Evidence indicates that dietary compounds that inhibit HDAC activity, such as curcumin, resveratrol, and berberine, show promise as anti-aging therapies, each with varying degrees of evidence.[11] [12] [13] A growing body of evidence indicates that beta-hydroxybutyrate is a robust HDAC inhibitor.[14]

Telomere attrition

"The exposome, the totality of non-genetic exposures a person experiences during a lifetime, profoundly influences telomere length and has diverse effects on human health." Click To Tweet

Telomeres are distinctive structures composed of short, repetitive sequences of DNA located on the ends of chromosomes. Telomeres form a protective "cap" – a sort of disposable buffer that gradually shortens with age – that prevents chromosomes from losing genes or sticking to other chromosomes during cell division.

Telomere length is commonly measured in leukocytes, a type of white blood cell. The length (in base pairs, see below) serves as a biomarker for a wide range of age-related disorders, including neurodegenerative disease, cardiovascular disease, and cancer, as well as all causes of premature death.[15] [16]

Base pairs are nitrogen-containing molecules (called nucleotides) that form the "rungs" of the ladder-like structure of DNA. The length of most telomeres ranges from 8,000 base pairs in a newborn to 3,000 base pairs in an adult and as low as 1,500 in older adults.[17] The average cell loses 30 to 200 base pairs from the ends of its telomeres each time it divides, contributing to (and serving as a marker of) aging.[18] When the telomeres on a cell's chromosomes get too short, the chromosome reaches a "critical length," and the cell stops dividing (senescence) or dies (apoptosis). Shorter telomeres leave DNA more vulnerable to mutations.

Telomerase, a reverse transcriptase enzyme, adds specific nucleotide sequences to the ends of existing chromosomes, extending the telomere. Telomerase activity is highly regulated during development, and its activity is almost undetectable in fully developed cells. This lack of activity causes cellular aging. If telomerase activates in a cell, the cell will continue to grow and divide or become "immortal," which is important for aging and cancer. Telomerase enzyme activity is detectable in more than 85 percent of human cancers.[19]

Telomere length is profoundly influenced by the exposome, the totality of non-genetic exposures a person experiences during a lifetime. The exposome comprises tangible and intangible exposures, ranging from food, air, physical surroundings, microbes, and chemicals to psychological stressors, education level, and financial status, among others, and likely has diverse effects on human health.

Assessing and quantifying the exposome presents challenges, but the length of telomeres may provide a suitable proxy for its assessment. For example, centenarians – people who live to be 100 years old or older – typically have longer telomere lengths than most adults in the 65- to 85-year range.[20] Longer telomeres are associated with several measures of good health. However, scientific evidence suggests that behaviors such as worry, rumination, and anticipatory stress switch on cardiovascular, hormonal, and immunological responses that shorten telomeres.[21]

Epigenetic alterations

Epigenetics is a biological mechanism that regulates gene expression (how and when specific genes turn on or off). Diet, lifestyle, and environmental exposures can drive epigenetic alterations throughout an individual's lifespan to influence health and disease and can even pass to subsequent generations. DNA methylation and histone modification are the primary biochemical processes that drive epigenetic alterations.

DNA methylation

DNA methylation occurs naturally when a methyl group – a chemical structure containing three hydrogen atoms and one carbon atom – attaches to one of DNA's four nucleotide bases (adenine [A], cytosine [C], guanine [G], or thymine [T]). Methylation creates a biological record of the varied molecular processes in human physiology. The primary methylation regulators are DNA methyltransferases and ten-eleven translocation (TET) enzymes.[22] Many lifestyle factors promote methylation, including dietary intake, exercise, stress, smoking, and others.[23] As a result, methylation is believed to be reversible.[24]

The most common DNA methylation process involves adding a methyl group to one of the carbon atoms in the cytosine base, forming 5-methylcytosine. This addition alters the overall geometry of the DNA strand, influencing gene expression. Most 5-methylcytosine is in areas of the DNA known as CpG islands – short stretches of DNA where the frequency of the cytosine-guanine (CG) sequence is higher than in other regions. Methylation of a CpG island in the promoter region of a gene turns off the gene's expression. DNA methylation may promote age-related diseases such as cancer.[24]

Histone modification

Histone modifications, which include acetylation, methylation, phosphorylation, and ubiquitination (as well as others)[25], regulate the activity of chromatin, the coiled structure DNA forms, preventing it from being opened and transcribed (the first step in gene expression and DNA replication) randomly. Chromatin wraps around histone proteins that open or close the chromatin depending on whether the histone has undergone modification. As modifications accumulate over the lifespan, chromatin is harder to open, and gene expression slows. HDAC inhibitors (described above) help release histones, open chromatin, prevent age-related losses in gene expression, and extend lifespan.[14]

Loss of proteostasis

Proteostasis is a homeostatic mechanism by which the body maintains the proteome, the collective set of proteins produced. The relationship between proteostasis and aging is complex and appears to be bidirectional. That is, aging drives the loss of proteostasis, and the loss of proteostasis promotes aging, a phenomenon seen in age-related neurodegenerative diseases, such as Alzheimer's disease, wherein misfolded proteins aggregate and, in turn, drive disease progression.[26]

Proteostasis involves a wide range of processes, including protein synthesis, folding, modification, transport, and degradation, among others.[27] These varied processes employ a network of cellular components, including chaperones (such as heat shock proteins)[28] and an array of cellular metabolites.[29]

Scientists have not fully characterized all the factors driving age-related proteostasis losses. However, several candidates have emerged, including accumulation of age-dependent protein damage, impairment of protein synthesis, inability to respond to altered proteostasis demands, and altered cellular metabolites related to age-dependent metabolic changes.[27]

Deregulated nutrient sensing

The body employs many sensing pathways that detect intra- and extracellular fat, amino acid, and sugar concentrations. During periods of food abundance, these pathways facilitate growth and storage, whereas during periods of scarcity, they trigger mechanisms that break down and mobilize internal stores. Nutrient sensing pathways are commonly dysregulated in aging but may be enhanced via dietary interventions, such as calorie restriction and intermittent fasting.[30]

Learn more about the beneficial metabolic effects of intermittent fasting in this episode featuring Dr. Mark Mattson.

Critical nutrient-sensing pathways that may become dysregulated with age include:

  • Mechanistic target of rapamycin (mTOR), a genetic pathway that senses amino acid concentrations and regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. mTOR integrates other pathways, including insulin, growth factors (such as IGF-1), and amino acids. It plays a crucial role in mammalian metabolism and physiology, with essential roles in the function of tissues, including the liver, muscle, white and brown adipose tissue, and the brain.

  • Adenosine monophosphate kinase (AMPK), a master regulator of cellular energy homeostasis. AMPK activation is triggered in response to altered aspects of mitochondrial performance, specifically elements of the electron transport chain. This activation, in turn, reduces the AMP/ATP ratio, promoting glycolysis (the breakdown of glucose). AMPK activation declines with aging, reducing autophagy and promoting inflammation.[31]

  • G-protein coupled receptors (GPR), a family of proteins that sense the presence of fatty acids. Interestingly, stimulation of specific GPRs induces pancreatic insulin release in response to glucose. Blocking the activity of these GPRs contributes to obesity in humans and mice.[32]

Mitochondrial dysfunction

Mitochondria are the primary organelle responsible for cellular energy production. Mitochondrial dysfunction is the loss of normal mitochondrial function over time as reactive oxygen species damage vulnerable mitochondrial membranes and energy production becomes less efficient.

The principal drivers of mitochondrial dysfunction include loss of inner membrane electrical and chemical potential, altered electron transport chain function, and reduced metabolite transport into the mitochondria.[33] Mitochondrial dysfunction is a driver of many chronic diseases, such as cancer, type 2 diabetes, and cardiovascular disease, and is a prominent feature of aging.[12]

Learn more about cellular senescence in our overview article.

Stem cell exhaustion

Stem cells are undifferentiated cells that have the potential to develop into specialized cells, such as muscle, blood, or brain cells, serving as a repair system for the body. Stem cells can divide and renew for a long time, but not indefinitely.

Stem cell exhaustion, the loss of stem cells' capacity to divide, occurs naturally over the lifespan due to various factors, including toxic metabolite accumulation, DNA damage, proteostasis failure, mitochondrial dysfunction, epigenetic remodeling, and environmental exposures.[34] [35] Rejuvenation therapies such as cellular reprogramming may compensate for the effects of stem cell exhaustion.[36]

Altered intercellular communication

Intercellular communication, or signaling, is essential for coordinating the many physiological processes in a multicellular organism. As cells age, they can become senescent, often acquiring a senescence-associated secretory phenotype, or SASP, a characteristic secretory pattern that influences cell signaling.[37] SASP is profoundly pro-inflammatory and immunosuppressive and contributes to inflammaging.[38]

Inflammaging

Inflammaging, a term coined by Dr. Claudio Franceschi, refers to chronic, low-grade inflammation that occurs with aging.[12] This form of inflammation is often referred to as "sterile" because it involves minor immune cell infiltration in the absence of a pathogen.[39] The processes that drive inflammaging and its associated pathological conditions are bidirectional and involve multiple physiological processes and pathways.

A fundamental component of the inflammaging process is the immune system's recognition of metabolic, hormonal, and immune stimuli (such as chronic infections or age-related changes in the gut microbiota), thereby promoting an inflammatory environment.[40] In addition, the cellular senescence (see "Cellular senescence" above) that accompanies aging activates pro-inflammatory signaling pathways and drives the release of cytokines, chemokines, and growth factors – evidence of the senescence-associated secretory phenotype (SASP) described above.[41] Other contributors to inflammaging are cellular debris from normal cell death and the accumulation of metabolic byproducts,[42] such as amyloid-beta proteins, which are involved in the pathogenesis of Alzheimer's disease.

Inflammaging likely drives the impaired immune response exhibited among older adults and is both a contributor to and a result of increased infections.[43]

Contributors to interindividual differences in the accumulation of hallmarks of aging

Diet

  • Sugar-sweetened soda consumption was associated with shorter telomeres among US adults. Conversely, 100 percent fruit juice consumption was associated with longer telomeres, while diet sodas and noncarbonated sugar-sweetened beverages were not associated with telomere length.[44]
  • A Western dietary pattern high in saturated fat intake and consumption of refined flour, red and processed meat, and sugar-sweetened beverages was associated with shorter telomeres. In contrast, a Mediterranean dietary pattern, rich in plant foods, fish, and seafood, was associated with longer telomeres.[45]
  • Diets high in antioxidants were associated with longer telomeres in children and adolescents.[46]
  • High blood sugar levels increased the rate of cellular senescence in bone marrow stem cells.[47]
  • Virgin olive oil reduced oxidation and DNA breaks compared to sunflower oil.[48]

Exercise

  • A sedentary lifestyle accelerated aging while exercising reduced cellular senescence.[49]
  • Resistance and endurance exercise increased the production of heat shock proteins, which are large structures that help other proteins maintain their shape, preventing the loss of proteostasis.[50]
  • Regular physical exercise altered DNA methylation patterns, a primary feature of epigenetic change.[50]

Temperature-induced biological stress

Human life is sustainable within a narrow range of temperatures, extending from approximately 27°C (80.6°F) to approximately 42°C (107.6°F). Exposure to temperatures outside this range induces cellular stress and subsequent compensatory responses that may have anti-aging effects.

For example, heat exposure via sauna use induces the activity of heat shock proteins, a large class of proteins that play prominent roles in many cellular processes, including immune function, cell signaling, cell-cycle regulation, and proteome homeostasis.[51] Heat shock proteins directly scavenge reactive oxygen species and support cellular antioxidant capacity through their effects on maintaining glutathione levels.[52] [53] In addition, heat shock proteins promote mitochondrial biogenesis,[54] potentially reversing age-related mitochondrial dysfunction. (See "Mitochondrial dysfunction" above)

Cold exposure via cold-water immersion or cryotherapy induces cold shock proteins, a large family of proteins that respond to cellular stressors such as cold exposure, DNA damage, and hypoxia.[55] Notable cold shock proteins include cold‐inducible RNA binding protein, which promotes cell survival and activates antioxidant enzymes under conditions of mild hypothermia (89.6°F [32°C]), and RNA binding motif 3, or RBM3, which may be neuroprotective.[56] [57] [58] Cold exposure also promotes mitochondrial biogenesis.ref doi='10.20463/jenb.2017.0020'

Supplements and medications

  • Supplementing 1.5 or 2.5 grams of marine omega-3s reduced oxidative stress and increased telomere length; however, telomere lengthening depended on the accumulation of omega-3s in the blood.[12]
  • Metformin, a medication for type 2 diabetes that reduces glucose production in the liver, activating nutrient-sensing pathways that become dysregulated with age.[59]

Other lifestyle factors

  • Sleep loss reduces the length of telomeres and increases cellular senescence.[60]

Topic articles

Episodes

Relevant publications

  1. ^ Franceschi, Claudio; Bonafè, Massimiliano; Valensin, Silvana; Olivieri, Fabiola; De Luca, Maria; Ottaviani, Enzo, et al. (2006). Inflamm-aging: An Evolutionary Perspective On Immunosenescence Annals Of The New York Academy Of Sciences 908, 1.
  2. ^ a b Kroemer, Guido; Serrano, Manuel; Blasco, María A; López-Otín, Carlos; Partridge, Linda (2013). The Hallmarks Of Aging Cell 153, 6.
  3. ^ Gómez-González, Belén; Aguilera, Andrés (2008). Genome Instability: A Mechanistic View Of Its Causes And Consequences Nature Reviews Genetics 9, 3.
  4. ^ Crane MM; Russell AE; Schafer BJ; Blue BW; Whalen R; Almazan J, et al. (2019). DNA damage checkpoint activation impairs chromatin homeostasis and promotes mitotic catastrophe during aging. Elife 8, .
  5. ^ Kuo LJ; Yang LX (2008). Gamma-H2AX - a novel biomarker for DNA double-strand breaks. In Vivo 22, 3.
  6. ^ Palla, Viktoria-Varvara; Karaolanis, Georgios; Katafigiotis, Ioannis; Anastasiou, Ioannis; Patapis, Paul; Dimitroulis, Dimitrios, et al. (2017). gamma-H2AX: Can It Be Established As A Classical Cancer Prognostic Factor? Tumor Biology 39, 3.
  7. ^ Greaves, Rebecca; Yu, Binbing; Ferrucci, Luigi; Seidman, Michael M.; Bohr, Vilhelm A.; Dunn, Christopher, et al. (2012). Age-Related Disease Association Of Endogenous γ-H2AX Foci In Mononuclear Cells Derived From Leukapheresis Plos One 7, 9.
  8. ^ Ciccia, Alberto; Elledge, Stephen J. (2010). The DNA Damage Response: Making It Safe To Play With Knives Molecular Cell 40, 2.
  9. ^ Nakad, Rania; Schumacher, Björn (2016). DNA Damage Response And Immune Defense: Links And Mechanisms Frontiers In Genetics 7, .
  10. ^ Pasyukova, E. G.; Vaiserman, Alexander (2012). Epigenetic Drugs: A Novel Anti-Aging Strategy? Frontiers In Genetics 3, .
  11. ^ Reuter, Simone; Gupta, Subash C.; Park, Byoungduck; Aggarwal, Bharat B.; Goel, Ajay (2011). Epigenetic Changes Induced By Curcumin And Other Natural Compounds Genes & Nutrition 6, 2.
  12. ^ a b c d Invalid citation for doi=10.1111/j. 1747-0285.2009.00781.x, please fix.
  13. ^ Kalaiarasi, Arunachalam; Anusha, Chidambaram; Rajasekaran, Subbiah; John Marshal, Jayaraj; Sankar, Renu; Muthusamy, Karthikeyan (2016). Plant Isoquinoline Alkaloid Berberine Exhibits Chromatin Remodeling By Modulation Of Histone Deacetylase To Induce Growth Arrest And Apoptosis In The A549 Cell Line Journal Of Agricultural And Food Chemistry 64, 50.
  14. ^ a b Edwards, Clare; Canfield, John; Copes, Neil; Rehan, Muhammad; Lipps, David; Bradshaw, Patrick C. (2014). D-beta-hydroxybutyrate Extends Lifespan In C. Elegans Aging 6, 8.
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  17. ^ DOI: 10.1016/s0531-5565(01)00218-2
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  19. ^ DOI: 10.2172/766184
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  22. ^ Takeshima H; Niwa T; Yamashita S; Takamura-Enya T; Iida N; Wakabayashi M, et al. (2020). TET repression and increased DNMT activity synergistically induce aberrant DNA methylation. J Clin Invest 130, 10.
  23. ^ Kusui, Chika; Kimura, Tadashi; Ogita, Kazuhide; Nakamura, Hitomi; Matsumura, Yoko; Koyama, Masayasu, et al. (2001). DNA Methylation Of The Human Oxytocin Receptor Gene Promoter Regulates Tissue-Specific Gene Suppression Biochemical And Biophysical Research Communications 289, 3.
  24. ^ a b Wang, Tina; Havas, Aaron; Ideker, Trey; Adams, Peter D.; Robertson, Neil; Field, Adam E. (2018). DNA Methylation Clocks In Aging: Categories, Causes, And Consequences Molecular Cell 71, 6.
  25. ^ Alaskhar Alhamwe, Bilal; Khalaila, Razi; Wolf, Johanna; Von Bülow, Verena; Alhamdan, Fahd; Hii, Charles S., et al. (2018). Histone Modifications And Their Role In Epigenetics Of Atopy And Allergic Diseases Allergy, Asthma & Clinical Immunology 14, 1.
  26. ^ Walther, Dirk M.; Kasturi, Prasad; Zheng, Min; Pinkert, Stefan; Vecchi, Giulia; Ciryam, Prajwal, et al. (2015). Widespread Proteome Remodeling And Aggregation In Aging C. Elegans Cell 161, 4.
  27. ^ a b Verma, Kanika; Verma, Monika; Chaphalkar, Aseem; Chakraborty, Kausik (2021). Recent Advances In Understanding The Role Of Proteostasis Faculty Reviews 10, .
  28. ^ DOI: 10.1016/0968-0004(94)90041-8
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  30. ^ Mattson, Mark P.; Moehl, Keelin; Ghena, Nathaniel; Schmaedick, Maggie; Cheng, Aiwu (2018). Intermittent Metabolic Switching, Neuroplasticity And Brain Health Nature Reviews Neuroscience 19, 2.
  31. ^ Salminen, Antero; Kaarniranta, Kai (2012). AMP-activated Protein Kinase (AMPK) Controls The Aging Process Via An Integrated Signaling Network Ageing Research Reviews 11, 2.
  32. ^ Ozawa, Kentaro; Tauber, Maithé; Maffeis, Claudio; Pouta, Anneli; Kiess, Wieland; Van Gaal, Luc, et al. (2012). Dysfunction Of Lipid Sensor GPR120 Leads To Obesity In Both Mouse And Human Nature 483, 7389.
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