Mitochondria: The unsung heroes of aging research

Najeeb S

The majority of bodily systems gradually alter as we age. Understanding the cellular and molecular mechanisms that underlie these alterations as well as those that coincide with the start of age-related illnesses is the main goal of research on the biology of aging. Experiments can be planned to better understand when and how pathological alterations start as scientists get a better understanding of these processes. This information will be crucial in the development of therapies to treat or prevent diseases. Significant progress has been made in understanding the structural and functional alterations that take place in many biological systems. Additionally, research has increased our understanding of the physiological elements linked to longer lifespans in both human and animal models. The biological basis of human aging remains one of the greatest unanswered scientific questions.

The earliest modern humans are typified by Homo sapiens, the last common ancestor of modern humans. Between 260,000 and 350,000 years ago, populations in East and South Africa are thought to have merged to form modern humans. In the context of aging research, it is important to note that the life expectancy in India has been steadily increasing, with a life expectancy of 70.62 years in 2024, marking a 0.29% rise from 2023, which itself saw a 0.33% increase from 2022, reaching 70.42 years. This upward trend underscores the significance of addressing age-associated health challenges to ensure a healthier aging population. Aging research, also known as biogerontology and more recently geroscience, has highlighted several promising interventions with potential clinical applications. These include dietary restrictions, exercise, mTOR (mammalian target of rapamycin) inhibitors, metformin and acarbose, NAD (nicotinamide adenine dinucleotide) precursors and sirtuin activators, as well as strategies targeting senescence, telomere dysfunction, hormonal factors, and mitochondrial-targeted therapeutics. Specifically, these interventions focus on improving mitochondrial function, energy production, and biogenesis, with an emphasis on mitochondria-targeted antioxidants and the benefits of NAD precursors.

Mitochondria, the double-membranous bean-shaped organelles buzzing with energy inside our cells found in the cytoplasm, are renowned as the powerhouses of eukaryotic cells due to their crucial role in cellular bioenergetics. These mitochondria are the unsung heroes (or villains) of the aging saga. Mitochondria are responsible for producing the energy that keeps our cells running, but as we age, they start to falter, leading to a cascade of age-related issues. As mitochondria age, they become less efficient at producing energy, leading to a decline in cellular function. This decline can manifest in various ways, from wrinkles and gray hair to more serious issues like heart disease and neurodegenerative disorders. No structure is more closely and concurrently linked to the vitality of youth and the deterioration of older people. Our understanding of mitochondria has gradually changed as a result of the discovery of their intricate and opposing roles. Mitochondria are now thought of as platforms for intracellular signaling, innate immunity regulators, and modulators of stem cell activity rather than as straightforward bioenergetic factories. Each of these characteristics, in turn, offers hints on how mitochondria may control aging and age-related illnesses.

Cellular and physiological functional loss is processed in conjunction with aging. It is believed that aging is primarily caused by the accumulation of damage over time. The focus lately has been on molecular damage in aging at the level of proteins, RNA, DNA, organelles, cells, and tiny molecules. Controlling cell death may play a significant role in aging regulation. Cell autophagy may have a role in health, aging, and disease; therefore, it is important to understand how to prevent age-related illnesses. Mitochondria play a crucial role in the aging process. Certain nuclear-encoded mitochondrial genes may help protect against age-related problems. When mitochondrial stress pathways do not work properly, it can disrupt cell and body balance. This can lead to issues like mutations in mitochondrial DNA (mtDNA) and imbalances in important metabolites. Recent research shows that keeping mtDNA intact through repair mechanisms is essential. These repairs are necessary for the electron transport chain to work properly in eukaryotic cells. Mitochondria are connected to human aging through three key aspects: their role in regulating the innate immune system, the mechanisms that link mitochondrial quality control to age-related diseases, and the potential influence of mitochondrial-to-nuclear signaling on the aging process. Mutations in mitochondrial DNA (mtDNA) can impair cellular respiration, leading to a range of progressive metabolic disorders known as “mitochondrial diseases.” The occurrence and persistence of mtDNA mutations in cells and tissues are closely associated with processes like DNA replication, DNA damage and repair, purifying selection, organelle dynamics, mitophagy, and aging. Therefore, mitochondria perform diverse functions and play significant roles in the aging process.

Studies on mtDNA copy numbers during aging have shown tissue-specific variations, with mtDNA levels decreasing in skeletal muscle but increasing in the liver, highlighting the complex relationship between mitochondrial dysfunction and age-related phenotypes. Research highlights the crucial role of mtDNA repair mechanisms in maintaining cellular stability and combating aging-related oxidative damage. Mitochondrial-specific repair processes, including base excision repair and mismatch repair, are vital for preserving mtDNA integrity and preventing age-associated mitochondrial dysfunction that can lead to various diseases, such as neurodegenerative disorders and cancer. Researchers are also studying mitophagy, the process of removing damaged mitochondria, to maintain cellular health. Evidence suggests that mitochondrial functions deteriorate with age, and mutations may result from oxidative stress, making cells more vulnerable. This oxidative stress can trigger mitochondrial permeability transition, leading to the release of cytochrome c and initiating apoptosis. Overall, mitochondrial dysfunction is believed to contribute significantly to aging-related changes in cells.

With researchers looking into novel therapeutic approaches to address mitochondrial malfunction, the future of mitochondrial research is bright. The creation of medications that can improve mitophagy and mitochondrial biogenesis is one promising approach that may prolong life expectancy and postpone aging. The possibility of lifestyle changes like exercise and calorie restriction to enhance mitochondrial function is also being investigated. Mitochondrial research isn’t just about understanding aging; it’s about finding ways to combat it. For example, enhancing mitochondrial function could help reduce wrinkles and improve skin elasticity, giving us all a chance to look a little younger. On a more serious note, improving mitochondrial health could also help prevent age-related diseases like Alzheimer’s, Parkinson’s, and cardiovascular disorders. So, the next time you look in the mirror and notice a new wrinkle or gray hair, remember the mitochondria. These tiny powerhouses are working overtime to keep your cells running, but they need a little help as they age. With ongoing research and innovative therapies, we might just be able to give our mitochondria the support they need to keep us looking and feeling young. Mitochondrial transplantation is a challenging but potentially ground-breaking option for the treatment of various mitochondrial pathologies, although several questions remain to be addressed before its application in mitochondrial medicine

Najeeb S is a Research Assistant at AcREM-Stem, University of Kerala