Overview (Molecules, Cells, Tissue)
1. Molecular alterations
• Cells consist of DNA, RNA, proteins, fats, and other small molecules
• These molecules can become damaged, blocking their function
• Some can be over-produced, building up aggregates (with a declining ability of cells to recycle these molecules)
2. Cellular dysfunction
• Cells must remain functional to contribute to the function of a tissue
• Networks of cellular processes can stop functioning, leading to a decline in organ function and health
3. Tissue degeneration
• Cells and molecules must support the function and integrity of tissue (balanced healthy state of homeostasis)
• Age-related changes can negatively impact entire tissue from achieving homeostasis
1. Molecular Alterations
1.1. Short telomeres
• Telomeres (repetitive DNA sequences at the end of chromosomes) shorten with each round of cell division
• When telomeres reach a sufficiently short length, cells lose their ability to reproduce
• This prevents runaway proliferation of otherwise cancerous cells, but also limits the regenerative potential of non-cancerous cells
• Extending telomeres has the potential to rejuvenate many types of cells (explicitly reducing the risk of cancer)
1.2. DNA damage
• DNA is under attack from endogenous and environmental factors
• Normally the resulting damage is recognized and corrected
• Repair errors and uncorrected insults can happen, leading to organelle dysfunction, loss of proteostasis, and deleterious outcomes
• DNA damage is the primary cause of almost all cancers
• Improving DNA repair is one of the best ways to prevent cancer
1.3. Disrupted proteostasis
• Cells constantly synthesize new molecules and break down old ones
• Multiple age-related changes can disrupt this balance, causing subcellular dysfunctions
• Restoring the proteostatic balance in organs / cells leads to rejuvenation
1.4. Loss of epigenetic information
• DNA provides the instructions for cells to carry out specific functions
• Accessibility of specific regions of DNA is determined by many factors including methylation and histone coiling
• These "epigenetic" factors change with age and can destabilize the programs cells use to access and use DNA to function appropriately
• Resetting the epigenetic signature of a cell to its original state can stimulate that cell to repair damage in its microenvironment
2. Cellular Dysfunction
2.1. Loss of tissue-specific stem cells
• Adult tissue depends on a small number of tissue-specific stem cells to replenish cells lost in the respective tissue throughout life
• Stem cells of multiple tissue decline in number, lose their proliferative capacity, or begin to produce daughter cells in an altered proportion
• Replacing those cells through cell therapies or stimulating divisions of existing stem cells can regenerate different tissue
2.2. Overarching cell growth signals
• The decision of a cell to rest or reproduce is driven by a complex interplay of intra-cellular and inter-cellular connections
• Some growth signals become abnormally activated with age, disrupting the normal balance of growth and inactivity in cells
• Reducing these growth signals lead to improvements in health-span and lifespan (specific therapeutics can deliver the same benefits on a molecular level)
2.3. Buildup of damaged cells
• Cells that undergo extensive damage normally commit themselves to death through the process of apoptosis
• Cells instead can avoid apoptotic cell death and become persistent
• These dysfunctional cells often secrete pro-inflammatory signals that can further damage neighboring tissue
• Removing these cells can both improve the function of individual tissue and extend health-span
2.4. Mitochondrial damage
• Mitochondria are the energy factories of cells and are critical to metabolic oxidation-reduction reactions
• Dysfunctional mitochondria can generate harmful reactive oxygen species or disrupt redox balance of critical coenzymes
• Restoring energy function in aged tissue is a key part of reversing the decline in tissue function
3. Tissue Degeneration
3.1. Buildup of extracellular aggregates
• Amyloids (fibril-shaped protein aggregates) can either contribute to normal function or cause disease, depending on protein content and context
• Accumulation of amyloids occurs in the aging brain and may cause Alzheimer's Disease
• Accumulation of many types of extracellular aggregates like amyloids occur in other organs with age as well and may contribute to reduced function
3.2. Non-regenerating adult tissue
• Tissue loses its capacity to repair shortly after birth, particularly the heart and the brain, where very limited repair can happen in the aged tissue
• Other tissue, such as the thymus and ovaries, age faster than the rest of the body and become exhausted early in life
• Reactivating, repairing, and preserving the function of this tissue opens new pathways to treating disease
3.3. Stiffening of extracellular matrix
• Cells live on a framework of proteins, fats, and large molecules (Extracellular Matrix, ECM)
• ECM components continuously renew, but chemical alterations can accumulate on low-turnover components or under stressful conditions (injury or infection)
• These changes modify local physical and signaling properties, which can compromise function of the tissue or cells within it
• Stiff ECM signals to the surrounding tissue create stiffer, scar-like ECM, pump out inflammatory molecules, and stop proper functioning of the nearby cells
3.4. Chronic inflammation
• Inflammation is a key part of an acute immune response
• With age, some immune cells never stop producing inflammatory signals, even when there is no infection present
• This chronic inflammation can keep a tissue in a permanent state of stress, which accelerates the accumulation of other age-related damage and contributes to the development of almost all major diseases of aging
3.5. Changes in endocrine signaling
• Distant cells communicate and coordinate through small molecules and proteins that circulate in the bloodstream
• With age, the relative levels of these endocrine factors in the blood change; some increase, and others decline quickly
• Several of these hormonal shifts have been shown to cause tissue dysfunction and restoring them to more youthful states can help keep the whole body functioning better