Telomeres are repetitive DNA sequences found at the end of human chromosomes, which 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. Therapies that extend telomeres have the potential to rejuvenate many types of cells, but the therapies must be designed explicitly to avoid the risk of cancer.

DNA regularly comes under attack from both endogenous and environmental factors. In most cases the resulting damage is recognized and corrected by quality control systems. However, repair errors and uncorrected insults arise at a low frequency and accumulate over the lifespan, which can lead to organelle dysfunction, loss of proteostasis, and other deleterious outcomes. DNA damage is the primary cause of almost all cancers, so improving DNA repair machinery is one of the best ways to prevent cancer from arising.

Our cells are constantly synthesizing new molecules and breaking down old ones in a process which must be carefully regulated. Multiple age-related changes can disrupt this balance, causing subcellular dysfunctions through the formation of harmful protein aggregates or mislocalization of proteins. Many different ways of restoring this proteostatic balance in old organs and cells have led to profound rejuvenation.

Our DNA provides the instructions cells need to carry out their specific functions. However, the 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 our 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.

Many adult tissues depend on a small number of tissue-specific stem cells to replenish cells lost in that tissue throughout life. As we age, the stem cells of multiple tissues 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 many different tissues.

The decision of a cell to rest or reproduce is driven by a complex interplay of intracellular and intercellular queues. Some growth signals, such as the mTOR pathway, become aberrantly activated with age, disrupting the normal balance of growth and quiescence in cells. Fasting and other methods of reducing these growth signals lead to dramatic improvements in healthspan and lifespan of animal models, and specific therapeutics can deliver those same benefits on a molecular level.

Cells that undergo extensive damage typically commit themselves to death through the process of apoptosis. In rare instances, cells instead avoid apoptotic cell death and become persistent. These dysfunctional cells, sometimes called "senescent cells," often secrete pro-inflammatory signals that can further damage neighboring tissue. Removing these cells can both improve the function of individual tissues and extend healthspan in animal models.

Mitochondria are the energy factories of our cells, and are critical to metabolic oxidation-reduction reactions. Dysfunctional mitochondria, which accumulate with age, can generate harmful reactive oxygen species or disrupt redox balance of critical coenzymes such as NAD(H). Restoring energy function in aged tissues is a key part of reversing a slide toward decline in tissue function.

Amyloids are fibril-shaped protein aggregates which can either contribute to normal function or cause disease, depending on their protein content and context. Accumulation of Amyloid-β, for example, 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.

Some of our tissues lose their capacity to repair shortly after birth, particularly the heart and the brain, where very limited repair can happen in the aged tissue. Other tissues such as the thymus and ovaries age faster than the rest of our bodies and become exhausted early in life. Figuring out ways to reactivate, repair, and preserve the function of these tissues can open new pathways to treating disease.

Our cells live on a scaffold of proteins, fats, and large molecules that we call the Extracellular Matrix, or the ECM. While ECM components continuously renew, chemical alterations can accumulate on low-turnover constituents or under stressful conditions such as injury or infection. These changes modify local physical and signaling properties, which can in turn compromise function of the tissue or cells within it. Stiff ECM signals to the surrounding tissues to create more stiff, scar-like ECM, pump out inflammatory molecules, and stop proper functioning of the nearby cells.

Inflammation is a key part of an acute immune response, but as we 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 nearly all of the major diseases of aging.

Distant cells communicate and coordinate with one another through small molecules and proteins that circulate in the bloodstream. As we age, the relative levels of these endocrine factors in the blood change; some increase, and others decline precipitously. 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.