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The Science of Aging:
1. Introduction:
2. Anatomical Changes Associated with Aging
Skin, Muscle, and Bone Deterioration
One of the most visible signs of aging is thinner, sagging skin that has lost its youthful elasticity. This is largely due to the flattening of the dermal-epidermal junction that occurs over time. Loss of muscle mass and tone (sarcopenia) also occurs, beginning as early as age 30. Bones lose mineral density and become frailer and more prone to fractures (osteoporosis).
Stiffening Blood Vessels
Arteries stiffen and lose elasticity with age, resulting in higher blood pressure and reduced circulation. The left ventricle of the heart also thickens in response (left ventricular hypertrophy). These vascular changes increase the risk of cardiovascular disease.
Lung Decline
Lung capacity and efficiency tend to decline steadily past young adulthood. Oxygen absorption into the bloodstream drops while residual volume increases. Coughing, shortness of breath, and impaired immunity in the lungs become more common.
Neural Degeneration
The brain undergoes neuronal loss, shrinks in volume, and experiences less blood flow as we age. Cognitive decline, dementia, and diseases like Alzheimer’s and Parkinson’s are increasingly likely in later life. Peripheral nerves in the body are also subject to gradual degeneration over time.
Accumulation of Senescent Cells
Senescent cells that have stopped dividing build up in tissues throughout the body as we age. They release inflammatory factors and enzymes that degrade the extracellular matrix, contributing to the aging process.
3. Cellular Hallmarks of Aging
Telomere Shortening
Telomeres are protective caps on the ends of chromosomes that shorten each time a cell divides. Once they reach a critically short length, cells stop dividing and become inactive (cell senescence). This contributes to tissue degeneration over time.
Mitochondrial Dysfunction
Mitochondria generate energy for cells and their function declines with age. This leads to less efficient metabolism and more oxidative stress within aging cells.
Stem Cell Exhaustion
The number and plasticity of tissue-specific stem cells decrease as we get older. This impairs the normal process of cellular renewal and regeneration.
Disrupted Cell Signaling
Protein Aggregation
Misfolded proteins accumulate within and around cells as protein homeostasis mechanisms deteriorate with age. These toxic aggregates contribute to many age-related diseases.
4. Genetic Influences on Aging
Longevity Genes
Specific genes like FOXO3, APOE, KLOTHO, and SIRT6 have variants associated with longevity in humans. They control cellular processes related to metabolism, antioxidation, and genome stability.
Epigenetic Shifts
Epigenetic changes to chromatin and DNA methylation patterns occur over time leading to altered gene expression. This affects cellular function and phenotype with age.
Genomic Instability
Accumulated damage to nuclear DNA and mitochondrial DNA leads to mutations and impaired genome integrity. DNA repair mechanisms also decline with age.
Signaling Pathways
Key genetic pathways like mTOR, insulin/IGF-1, and Klotho/FGF regulate aging. Alterations affect nutrient sensing, metabolism, growth, and stress resistance over the lifespan.
Sirtuins and NAD+
Sirtuin proteins regulated by NAD+ levels play a role in healthy aging through their effects on inflammation, mitochondrial function, circadian rhythms, and metabolism.
5. Cellular and Molecular Mechanisms of Aging
Inflammaging
A chronic low-grade inflammation mediated by IL-6, TNF-a, COX enzymes, and NF-kB signaling occurs during aging called “inflammaging”. This contributes to many age-related diseases.
Glycation
Sugars can spontaneously react with proteins and lipids to form advanced glycation end products (AGEs) that accumulate during aging. This leads to loss of protein and tissue function.
Proteostasis Decline
The breakdown of proteostasis leads to toxic protein aggregation and cellular dysfunction during aging. Impaired autophagy and inadequate protein degradation contribute.
Metabolic Dysregulation
Aging cells experience reduced insulin sensitivity, altered nutrient sensing through mTOR, and mitochondrial changes that affect energy production and metabolism. Fat tissue accrual also increases.
Stress Response Attenuation
Cells lose resilience and the ability to activate protective stress response pathways involving sirtuins, heat shock proteins, antioxidant enzymes, etc. This makes cells more vulnerable to damage.
6. Cutting-Edge Research into Life Extension
Senolytic Therapies
Senolytic drugs selectively eliminate senescent cells and have shown promise in improving age-related conditions in animal models. Human trials are now underway.
Stem Cell Therapies
Introducing new functional stem cells into aged tissues may rejuvenate them and restore lost regenerative capacity. This includes mesenchymal, neural, and hematopoietic stem cells.
NAD+ Boosters
Increasing cellular NAD+ level activates sirtuins and other protective genes. This improves mitochondrial health and various markers of aging in pre-clinical studies.
mTOR Inhibitors
Inhibiting mTOR signaling shows potential for upregulating autophagy, improving proteostasis, and conferring longevity benefits based on animal research.
Cellular Reprogramming
Reprogramming aged cells into youthful induced pluripotent stem cells or directly converting cell types represent regenerative anti-aging approaches.
Tissue Engineering
Engineered tissues, lab-grown organs, and the development of artificial extracellular matrix materials may eventually help regenerate aged organs.
AI for Drug Discovery
Leveraging AI and deep learning to analyze large biological datasets and discover new targets, biomarkers, and drugs to modulate the aging process and extend HealthSpan.
7. Conclusion
The science of aging has advanced significantly in recent decades, though much remains unknown. New understandings of what happens to our cells, tissues, genes, and molecules over time has unveiled promising ways we may mitigate, slow, or treat age-related decline in the future. Though human longevity has increased, further progress relies on dedicated aging research and funding. By supporting this work, we increase our prospects for living not just longer, but healthier.
8. Q&A
What are some visible signs of aging?
Some of the most noticeable signs of aging include thinner, sagging skin, wrinkles, loss of muscle mass and strength, increased body fat, brittle bones, duller hair, and slower reflexes. Visual cues like greying hair and hair loss are also key signs of aging.
How do arteries change with age?
Arteries stiffen and lose elasticity as we age. This leads to increased blood pressure and reduced circulation. Atherosclerotic plaques may also build up in arteries, restricting blood flow.
What happens to lung function over time?
Lung capacity and efficiency decrease with age. Oxygen absorption into the blood drops while residual volume increases. Coughing fits, shortness of breath, and impaired immunity become more common.
Why is the brain impacted by aging?
The brain shrinks in volume and has reduced blood flow with age. Neurons die off and connections weaken over time leading to cognitive decline. Dementia and Alzheimer's disease become more likely.
How do telomeres relate to aging?
Telomeres shorten each time a cell divides. Critically short telomeres signal cells to stop dividing and enter senescence. This disrupts tissue renewal and contributes to aging.
What causes inflammaging?
Inflammaging refers to chronic low-grade inflammation in aging tissues mediated by inflammatory factors like IL-6, TNF-a, COX, and NF-kB signaling. It is linked to many age-related diseases.
How do AGEs accelerate aging?
Advanced glycation end products (AGEs) form from sugar reactions with proteins and lipids. AGE accumulation creates dysfunction and oxidative stress, contributing to faster aging.
What is proteostasis?
Proteostasis refers to protein homeostasis - the regulation of protein synthesis, folding, aggregation, and degradation. Its breakdown during aging leads to toxic protein buildup in cells.
How might cellular reprogramming combat aging?
Reprogramming aged cells into youthful pluripotent stem cells or other cell types represents a potential regenerative anti-aging strategy.
What is a key goal of geroscience research?
A key goal is to understand molecular drivers of aging to develop interventions that extend human health span and help prevent/treat age-related chronic diseases.
9. References
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- Niccoli, Teresa, and L. Partridge. "Ageing as a risk factor for disease." Current Biology vol. 22,17 (2012): R741-52. doi:10.1016/j.cub.2012.07.024
- Kennedy, Brian K., et al. "Geroscience: linking aging to chronic disease." Cell vol. 159,4 (2014): 709-13. doi:10.1016/j.cell.2014.10.039
- Lopes-Pereira, Ana B., et al. "Cellular senescence: A promising target for pharmacological modulation." Biochemical Pharmacology vol. 186 (2021): 114429. doi:10.1016/j.bcp.2021.114429
- Ocampo, Alejandro, et al. "In vivo amelioration of age-associated hallmarks by partial reprogramming." Cell vol. 167,7 (2016): 1719-1733.e12. doi:10.1016/j.cell.2016.11.052
- Singh, Prince PS, and Aditi Singh. "Biomarkers of aging: From function to molecular biology." Trends in Molecular Medicine 26.2 (2020): 164-178. doi:10.1016/j.molmed.2019.11.008
- Zhavoronkov, Alex, and Bhupendra K. Trivedi. "Geroprotectors: The drugs that can help fight aging—A mini review." Clinical Pharmacology & Therapeutics vol. 107,1 (2020): 60-65. doi:10.1002/cpt.1637
- Sierra, Fabio, and Pinchas Cohen. "Aging stem cells: Current approaches to counteracting stem cell aging." Wiley Interdisciplinary Reviews: Systems Biology and Medicine vol. 10,4 (2018): e1408. doi:10.1002/wsbm.1408
- Sharpless, Norman E., and Ronald A. DePinho. "How stem cells age and why this makes us grow old." Nature Reviews Molecular Cell Biology vol. 8,9 (2007): 703-13. doi:10.1038/nrm2241
- Campisi, Judith. "Aging, cellular senescence, and cancer." Annual Review of Physiology vol. 75 (2013): 685-705. doi:10.1146/annurev-physiol-030212-183653