A multifaceted approach to expanding healthspan
Cambrian is developing a pipeline of new therapies that selectively target the nine hallmarks of aging, designed to repair the damage that accumulates in our bodies as we age.
The Hallmarks of Aging
By building new medicines that target the mechanisms underlying disease, we can treat damage at the molecular level long before symptoms manifest – a transformative approach to medicine that Cambrian is leading. 
Our cells consist of DNA, RNA, proteins, fats, and other small molecules. Some of these molecules are long-lived and become damaged over time, impeding their function; others are over-produced as we age, building up and forming aggregates as the ability of our cells to recycle these molecules declines.
Our organs and tissues consist of trillions of cells, each of which has a life of its own. Cells must remain healthy and functional to contribute to the overarching function of a tissue. However, as we age, whole networks of cellular processes can stop functioning leading to a decline in organ function and health.
The ultimate job of our cells and molecules is to uphold the function and integrity of our tissues, allowing for a balanced healthy state called homeostasis. Three categories of age-related changes can negatively impact entire tissues from achieving this balance.
 Adapted from López-Otín, C., et. al., Cell. 2013 Jun 6; 153(6): 1194–1217.
Our genome changes in two critical ways as we age: (1) DNA mutations, and (2) telomere shortening. DNA mutations are the root causes of cancer, and the accumulation of many different mutations is what makes a cancer complex and aggressive enough to kill us. The ends of our chromosomes, called telomeres, shorten with every cell division, which helps to protect us from cancer but also limits the regenerative potential of non-cancerous cells.
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.
Intra and extra cellular aggregate buildup
Our cells are constantly synthesizing new molecules and breaking down old ones, and the balance between creation and breakdown must be carefully regulated. As we age, our ability to properly balance manufacturing new molecules and recycling others declines, leading to buildups of unwanted aggregates of proteins that can cause harm to our cells and their environment.
Cells that have undergone extensive DNA damage often commit apoptosis, or cellular suicide. However, sometimes cells that would normally enter apoptosis fail to do so, and instead enter a permanent and harmful state called cellular senescence. Cleaning up senescent cells can improve the function of an aged tissue.
Mitochondria are the energy factories of our cells. Cellular dysfunction is commonly linked to the inability of our cells to produce enough of the right kind of energy. Aged mitochondria do not effectively produce energy, they create large amounts of damaging reactive oxygen species, and they stop dividing at sufficient numbers to meet the energy requirements of a cell. Targeting these mechanisms can make cells healthier and longer lived.
Inadequate stress response
Cells are constantly reading signals from their environment and adapting their functions to respond properly to those signals. This can include signaling from hormones, an abundance or lack of nutrients, or damage to the cell’s environment. As we age, the ability of our cells to react to those stressors and to respond appropriately can decline in some key areas. By identifying and repairing the signaling pathways most dysregulated with age, we can restore the adaptive functionality of older cells.
Sustained tissue inflammation
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.
Disrupted tissue architecture
Our cells all live on a scaffold of proteins, fats, and large molecules that we call the Extracellular Matrix, or the ECM. The ECM must be continuously refreshed to keep a tissue organized, elastic, and sending the right signals to its cells. When the ECM is disrupted by injury, infection, or another cause it can have cascading negative effects to otherwise healthy cells within the tissue.
Stem cell exhaustion
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, stem cells can reach the limit of how many damaged cells they are able to replace. Enhancing these stem cells or adding new tissue-specific stem cells can replenish this pool and support better function in aging tissues.
The Neuroscience of Aging: Assessments, Treatments and Modeling in Aging and Neurological Disease - Chapter 46: Modeling Nutrition and Brain Aging in Rodents
Aging is the greatest risk factor for most neurodegenerative diseases including dementia. Nutrition has a profound impact on aging, and certain dietary interventions may have the potential to reduce the risk of neurodegenerative disease. Caloric restriction (CR) is one of the most robust nutritional interventions to improve brain health during aging; however, the relative contributions to the effects of CR of reduced energy intake, one or several macronutrients (protein, carbohydrate, or fat) or periods of fasting are unknown. The geometric framework (GF) has been used to determine the role of macronutrient intake on health and life span in mice with results indicating that ad-libitum low-protein, high-carbohydrate diets positively influence health and life span in model organisms. The GF may also be used to investigate the influence of macronutrient intake on brain health in aging rodents.
Nature Reviews - Drug Discovery (May 2021 Cover Story): Strategies for delivering therapeutics across the blood–brain barrier (Georg Terstappen; EVP, Drug Discovery)
A review of recent developments and challenges related to selected blood–brain barrier-crossing strategies — with a focus on non- invasive approaches such as receptor-mediated transcytosis and the use of neurotropic viruses, nanoparticles and exosomes — and analysis of their potential in the treatment of CNS disorders.
Nanoscale Advances (May 2021 Cover Story): Trafficking of JC virus-like particles across the blood–brain barrier (Georg Terstappen; EVP, Drug Discovery)
A study on John Cunningham virus-like particles (JC VLPs) and their potential use in developing a delivery system for transport of genes and small molecule cargoes across the blood-brain barrier (BBB).