{
  "titles": [
    "2020 - Clinical Genetics and Genomics of Aging.pdf",
    "2020 - Clinical Genetics and Genomics of Aging.pdf",
    "2011 - Mitochondrial genome deletions and minicircles.pdf",
    "2020 - Transposable elements, circular RNAs and mitochondrial.pdf",
    "2020 - Clinical Genetics and Genomics of Aging.pdf",
    "2020 - Clinical Genetics and Genomics of Aging.pdf",
    "2020 - Clinical Genetics and Genomics of Aging.pdf",
    "2020 - Clinical Genetics and Genomics of Aging.pdf",
    "2020 - Clinical Genetics and Genomics of Aging.pdf",
    "2017 - Independent impacts of aging.pdf"
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    "abolic regulation through mitochondrial signaling. Am J Physiol Endocrinol Metab.  2014;306:E58191.  74. Zhang R, Wang Y , Ye K, Picard M, Gu Z.Independent impacts of aging on mitochondrial DNA  quantity and quality in humans. BMC Genomics. 2017;18:890.  75. Hebert SL, Lanza IR, Nair KS.Mitochondrial DNA alterations and reduced mitochondrial  function in aging. Mech Ageing Dev. 2010;131:45162.  76. Liu D, Li H, Lu J, Bai Y .Tissue-specific implications of mitochondrial alterations in aging.",
    "mechanisms that lead to mitochondrial metabolism shifts in human aging are not  completely understood, the literature reports that the failure in the mitochondrial  metabolism of aged heart might be associated with mutations in the mtDNA.In this  sense, the aged heart shows an increase over 15-fold on mtDNA mutations in com- parison to hearts from young people [101]. Mutations in genes that encode Polg-a,  responsible for mtDNA repair machinery, cytochrome b, and several subunits of",
    "22. Fleming JE, Miquel J, Cottrell SF, Yengoyan LS, Economos AC: Is cell aging caused by respiration-dependent injury to the mitochondrial genome?Gerontology 1982, 28:, 44-53. 23. Pak JW, Herbst A, Bua E, Gokey N, McKenzie D, Aiken JM: Mitochondrial DNA mutations as a fundamental mechanism in physiological declinesassociated with aging. Aging Cell 2003, 2:1-7. 24. Jacobs HT: The mitochondrial theory of aging: dead or alive. Aging Cell 2003, 2:11-17.",
    "Sun., N, Youle, R. J. and Finkel, T. (2016). The mitochondrial basis of aging. Mol. Cell 61, 654-666. doi:10.1016/j.molcel.2016.01.028 Symer, D. E., Connelly, C., Szak, S. T., Caputo, E. M., Cost, G. J., Parmigiani, G. and Boeke, J. D. (2002). Human L1 retrotransposition is associated with genetic instability in vivo. Cell110, 327-338. doi:10.1016/S0092-8674(02)00839-5 Szabo, L., Morey, R., Palpant, N. J., Wang, P. L., Afari, N., Jiang, C., Parast,",
    "limitations to study mitochondrial metabolism in human samples, in this section  we briefly described the implications of mitochondrial metabolism for aging in  the most studied and high energy demand human tissues, such as skeletal muscle,  heart, and brain.Table 4.1 Main mitochondrial dynamics proteins that are altered in human tissues during the  aging process Tissue/ organ Fission Fusion Biogenesis Mitophagy Refs Skeletal  muscleIncreased  fragmentation Decreased Drp1  proteinIncreased  interconnected",
    "96. Wei Y-H, Wu S-B, Ma Y-S, Lee H-C.Respiratory function decline and DNA mutation in  mitochondria, oxidative stress and altered gene expression during aging. Chang Gung Med J.  2009;32:11332.  97. Kates AM, Herrero P, Dence C, Soto P, Srinivasan M, Delano DG, Ehsani A, Gropler  RJ. Impact of aging on substrate metabolism by the human heart. J Am Coll Cardiol.  2003;41:2939.  98. Gmez LA, Monette JS, Chavez JD, Maier CS, Hagen TM.Supercomplexes of the mito-",
    "phenotype, such as the Mitochondrial Free Radical Theory of Aging (MFRTA), and  although these theories have been recently confronted, the role of mitochondria in  the aging process is undeniable because of their versatile roles and implications  for cellular function. MFRTA suggests that the oxidative damage of mtDNA is the  key event disturbing the respiratory chain proteins to induce its dysfunction and  increase ROS production in a vicious cycle [123]. However, alterations in mito-",
    "102. Zhang R, Wang Y , Ye K, Picard M, Gu Z.Independent impacts of aging on mitochondrial  DNA quantity and quality in humans. BMC Genomics. 2017;18:890. https://doi.org/10.1186/ s12864-017-4287-0.  103. Norddahl GL, et al. Accumulating mitochondrial DNA mutations drive premature hema- topoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell.  2011;8:499510. https://doi.org/10.1016/j.stem.2011.03.009.",
    "78 p53, which regulate the catalytic subunits of ETC complexes [103]. Unfortunately,  these data have only been observed in murine models of aging and require further  verification in human samples.  Mitochondrial Metabolism intheAged Brain In normal conditions, the brain consumes around 25% of the total body glucose via  glycolysis and mitochondrial OxPhos [104]. So besides the mitochondrial dynam- ics dysfunctions described above, during aging there is also a decline in energy",
    "mitochondrial DNA mutations can reduce lifespan. Sci Rep. 2014;4:6569. 20. Ross JM, Stewart JB, Hagstrm E, Bren S, Mourier A, Coppotelli G, Freyer C, Lagouge M, Hoffer BJ, Olson L. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature. 2013;501(7467):412 5. 21. Sondheimer N, Glatz CE, Tirone JE, Deardorff MA, Krieger AM, Hakonarson H. Neutral mitochondrial heteroplasmy and the influence of aging. Hum Mol Genet. 2011;20(8):1653 9."
  ],
  "answer": "Alterations in the mitochondrial genome and bioenergetics significantly influence the aging process in humans through several mechanisms:  1. **Mitochondrial DNA Mutations**: As humans age, there is an increase in mitochondrial DNA (mtDNA) mutations. These mutations can lead to a decline in mitochondrial function, which is a fundamental mechanism in the physiological declines associated with aging [3]. Specifically, the aged heart shows a significant increase in mtDNA mutations compared to younger hearts, which may contribute to the failure in mitochondrial metabolism observed in aging [2].  2. **Respiratory Function Decline**: Aging is associated with a decline in respiratory function and increased oxidative stress, which can lead to further DNA mutations and altered gene expression in mitochondria [6]. This decline in mitochondrial respiratory function is linked to the production of reactive oxygen species (ROS), which can damage mtDNA and exacerbate mitochondrial dysfunction [7].  3. **Mitochondrial Dynamics**: Changes in mitochondrial dynamics, such as increased fragmentation and decreased fusion, are observed in aging tissues like skeletal muscle, heart, and brain. These alterations can impair mitochondrial biogenesis and mitophagy, leading to reduced energy production and increased cellular stress [5].  4. **Bioenergetic Shifts**: The aging process involves shifts in mitochondrial metabolism, particularly in high-energy-demand tissues. For example, the brain experiences a decline in energy production due to mitochondrial dysfunction, which can affect cognitive function and overall brain health [9].  Overall, the accumulation of mtDNA mutations, decline in mitochondrial respiratory function, and alterations in mitochondrial dynamics and bioenergetics contribute to the aging process by impairing cellular energy production and increasing oxidative stress, leading to cellular and tissue dysfunction.",
  "question": "How do alterations in the mitochondrial genome and bioenergetics influence the aging process in humans?"
}