Aging is the ultimate risk factor for most diseases, such as cancer, neurodegenerative, cardiovascular, diabetes, degenerative fibrosis and many others. When we are young, we are typically healthy, despite a predisposition that will lead inevitably to a specific degenerative condition. However, the degenerative processes do not kick in until a certain age, when we are older. It looks like when we are younger, the body can compensate cumulative stress and damage caused to our cells in the tissues, allowing to maintain that equilibrium, called homeostasis, that keeps our organs functional and healthy. However, over time this buffering capacity becomes thinner and thinner, until things wear off: our tissues stop working as they used to. These changes are typically caused by an initial small number of rare but bad cells, that progressively increase over time, causing additional damage to the good cells that eventually stop working efficiently, causing a vicious cycle. Eventually the bad cells take over leading to the onset of a disease.

Our body is equipped with a number or regenerative and healing functions. Some are intrinsic in every cell, such as DNA repair mechanisms that are triggered when something compromises the integrity of our genomic structures. These are important functions that enable a cell, for example when it replicates, to repair errors and other damages that might have happened to our DNA. For example, two large proteins called ATM and ATR, involved in the cellular response to DNA damage, are responsible to maintain genomic instability caused by intrinsic and external DNA-damaging agents, such as UV light or various chemicals and toxins. A lack of functions of these proteins results in progressive neurodegeneration, immunodeficiency, predisposition to malignancy or radiation sensitivity. Mutations on the genes encoding these proteins can cause premature aging and premature development of these diseases, but this occurs also naturally, over time.

Cells also have an intrinsic immune system, producing factors called interferons employed by the cells as antiviral agents and to modulate other immune functions. It can be triggers by a viral infection so when a cell is infected will release interferons, protecting the neighbor cells against potential infection. Interferons can also suppress growth of blood vessels preventing tumors to get nutrients and growing. They can also activate immune cells so they can better fight viruses, tumors and others agents. Unfortunately, an age-related decline or impaired innate interferon functions in the cells results in a number of negative consequences in the body, such as increased susceptibility of the elderly to infections, tumors and damage.

In the body there are several cell types responsible to keep the tissues in check. The immune system is specialized to recognize remove and remember damaging agents. Those could be external, such as virus, bacteria or parasites, or internal, such as tumorigenic cells or senescent cells (see below). The immune system is a very sophisticated network of cell types, intercommunicating with each other to maintain the body clean from damaging factors. As we age the immune system also ages and loses capacity to recognize or responding to these damaging agents. It also become exhausted by an increasing chronic inflammation that progressively accumulate as we age, phenomenon also called inflammaging.

Another important repairing mechanism is the regenerative tissue functions, driven by the stem cells. Those cells are progenitor cells, often dormant in a quiescent state in the tissue and waiting to be activated by some damage. Stem cells are critical because once activated they can generate a progeny of daughter cells capable of re-growing the damaged tissue back to its original structure and function. Stem cells have another important function: they can regenerate themselves, in a process called self-renewal. This is important so that the new repaired tissue can repeat the process if a new damage occurs. The regenerative capacity of our body is remarkable, allowing our tissues to keep their integrity, health and functions. However, over time also stem cells age or respond to the aged microenvironment where they live (called the niche), and they become less efficient to repair tissues or to self-renewing. As a result, our tissues change, become atrophic, fibrotic or dysfunctional leading eventually to diseases.

In regenerative medicine, the application of stem cells resulted of the generation of multiple new therapeutic opportunities. A promising area uses stem cells to generate bioengineering strategies to grow new tissues in a petri dish to be then transplanted in the body to repair damaged tissues. Some applications are already in clinical use, such as for skin grafts. Many others are on their way, either in preclinical development or in clinical trials for many different tissue types and for different clinical indications.

Another promising stem cells application is the direct transplantation into damaged tissues, where they can grow and engraft repairing. However, as we age stem cells become less efficient. What if we If we could rejuvenate them? We could restore their capacity to repair our tissues and maintain homeostasis. Promising and exciting strategies are advancing in that direction. For example, we and others showed that it is possible to reprogram epigenetically a cell so it can become the younger and healthier version of itself (Sarkar et al., 2020). This is a mechanism that every cell has encoded in its DNA, but normally works only in the germline (the sperm and the egg) during the embryogenesis to make sure that the cellular clock is turned back to zero, before initiating the cellular programs to generate the embryo. This important for example to prevent making old newborn babies. This intrinsic rejuvenative mechanism is locked in the other somatic cells of the body. We found it is possible to re-activate it transiently and safely, without changing the identity of the cell, enabling to push back the cellular clock of aged human cells to make them healthier and restore their functions. These technologies are under development to be translated into therapeutics with the promise that one day could rejuvenate the aged cells in the body so they can become the younger version of themselves, repeating the process over time when needed.

Among many of the drivers of the aging process, there is one that seems to stands out as the lower hanging fruit among the emerging space of the longevity therapeutics. This is cellular senescence. Every damage that occurs to the cells in our body can push the cells to stop what they are doing and activate a safety mechanism that locks them into an arrested state called cellular senescence. Senescent cells cannot replicate anymore preventing them to cause additional damage, such as becoming cancer cells. All sort of damage can trigger this response leading to cellular senescence such as, oxidative stress, mitochondrial dysfunctions, DNA damage, viral infection, cigarette smoking, pollutions, chemicals, etc. They all can induce that safety lock and push damage cells to become senescent.

Senescent cells dont die easily but they stick around in the tissue, accumulating slowly over time. Importantly, cellular senescence is a pleiotropic mechanism, meaning it can be both good or bad. When we are young, we can efficiently get rid of senescent cells. The body uses them positively such as for tissue repair, wound healing or tissue remodeling. However, as we age, and our immune system ages (partially trough cellular senescence, a phenomenon called immune-senescence), our body become less efficient in removing senescent cells, which then start to accumulate.

Being able to make a new generation of drugs that are very selective for senescent cells, will enable the promise to achieve rejuvenative clinical results in humans similarly to what we found in preclinical results. On that end, we recently published a targeted strategy with the goal to advance the field in that direction (Doan et al., 2020). Using a prodrug, we engineered a small molecule to generate a selective senolytic compound to develop a targeted therapy. This prodrug is inactive in non-senescent cells but activated by senescent cells, taking advantage of an enzymatic function of those cells. In geriatric mice this prodrug showed to be well tolerated but also efficacious to clear senescent cells, resulting in restored cognitive functions, muscle functions, stem cells functions, vitality and overall health. As we advance senolytic drugs to the clinic to treat age-related diseases, it is very important to be mindful that elderly individuals, who are frail, with co-morbidities and exposed to multiple medications, will not well tolerate drugs that are not safe and effective. Importantly, not all senescent cells are the same. They are rare, interspersed in the tissues but are also very heterogeneous. Being able to hit the right senescent cells, in the right diseased tissue will be key to enable effective therapies. Developing drugs that are very potent, selective and potent and safe will be pivotal.

The longevity therapeutics space is emerging, but is already disrupting the medical industry. The goal of longevity therapeutics is not just to add years to life, extending lifespan. The true goal is to add life to years and extend health span. A target that gets closer every day.

Marco Quarta is CEO, Rubedo Life Sciences.

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The Rise of Longevity Therapeutics - Pharmaceutical Executive