Professor and Head of the Campisi Lab at the Buck Institute
Many people know that aging is the biggest risk factor for cancer, but fewer know why. Judith Campisi, PhD, has been a pioneer developing our understanding of the basic biological mechanisms underlying this relationship. Today, Dr. Campisi is a Senior Scientist at the Lawrence Berkeley National Laboratory and a Professor at the Buck Institute for Research on Aging, where she continues to explore the aging process and cancer. Among many other honors, Dr. Campisi is the recipient of an AFAR Research Grant. She recently answered some of Infoaging's questions about cancer and aging.
What is the relationship between cancer cells and aging cells?
Cancer cells, in contrast to most ‘aging’ cells, actively kill an organism by giving rise to a lethal (malignant) tumor containing cells with new (albeit aberrant) properties. In order to form a malignant tumor, cancer cells must acquire somatic mutations – permanent changes in their DNA sequence, which they acquire mostly as they proliferate (grow) during the organism’s adulthood. These mutations allow cancer cells to develop the new properties that make it malignant. These new properties include1:
Cancer cells are typically genomically unstable – that is, in contrast to normal cells in which mutations occur at a low rate, cancer cells acquire mutations at a higher-than-normal rate2. As a consequence of this genomic instability, cancer cells often harbor dozens to hundreds of mutations. The nature and combination of these mutations determines which oncogenic properties a given cancer cell acquires, as well as the robustness of those properties. Cells with one or a few of these oncogenic properties are generally considered pre-cancerous or pre-malignant, whereas cells with many oncogenic properties are considered to be aggressive, malignant cancers.
Cellular senescence...is likely to be a double-edged sword
Aging cells are a vague term and depend on the context. In certain tissues, some cells (for example, mature neurons in the brain) exist for many years; during this time they may continue to function properly, lose their ability to function, or even die. In other tissues (for example, the skin, intestines, or bone marrow), cells continually proliferate, differentiate and die and do so from very early ages and throughout life. In such tissues, aging may be due to a combination of changes to the stem or progenitor cells that keep the tissue in an active state of proliferation and differentiation. It can also be due to changes in the tissue environment, which is crucial for maintaining stem cells number and quality. In these tissues, the age-related changes can be degenerative – that is the cells lose functional properties. However, age-related changes can also be oncogenic – that is, the stem or progenitor cells can acquire mutations that confer on them pre-cancerous or cancerous properties3.
Cellular aging also has another meaning. When cells that can divide experience potentially oncogenic insults or mutations, it can respond by undergoing an essentially permanent arrest of cell growth termed cellular senescence4. Cellular senescence is also sometimes (inappropriately) termed cellular aging. Cellular senescence or the senescence response probably evolved primarily to suppress the development of cancer – certainly, any process that prevents cell growth obviously also prevents lethal tumor formation.
Cellular senescence, however, is likely to be a double-edged sword. While there is firm evidence that it suppresses cancer, there is also mounting evidence that senescent cells, which accumulate with age and at sites of age-related disease, can have deleterious effects5. Prominent among these deleterious effects is the ability to secrete high levels of proteins that can disrupt the normal tissue microenvironment. Among the factors secreted by senescent cells – the so-called senescence-associated secretory phenotype or SASP – are numerous inflammatory cytokines, growth factors and proteases.
Several lines of evidence suggest that the SASP can indeed disrupt normal tissue structure and function, thereby contributing to age-related phenotypes and diseases. Ironically, the SASP of senescent cells can also promote normal and precancerous cells to adopt more aggressively malignant properties6. Thus, cellular senescence suppresses cancer early in life, thereby promoting longevity. However, as senescent cells accumulate, they can promote aging and age-related pathology.
Why does the risk of many cancers increase with aging? Why does the risk of cancer decline after the age of 80?
There are two fundamental conditions that are required in order for cancer cells to form a lethal tumor.
The first, as discussed above, is mutations. Cancer cells must acquire numerous somatic mutations in order to develop the malignant properties that render them deadly. It takes time to acquire those mutations. However, potentially oncogenic mutations begin to accumulate surprisingly early in life, decades before the incidence of cancer begins to rise significantly (at about the mid-point of the life span, or 50-60 years of age for humans)7. It has therefore long been suspected that something else must happen (a second condition) in addition to an accumulation of mutations in order for most cancers to progress to full blown malignancy.
There are still many unanswered questions regarding the relationship between aging and cancer.
It is now clear that the second condition is the tissue environment. Normal tissue environments tend to suppress the development of cancer8, whereas disrupted tissue microenvironments – whether through injury, chronic inflammation or other causes – tend to favor tumor progression. Aging, of course, alters tissues in both obvious and not-so-obvious ways. One hallmark of aging tissues is chronic inflammation. The source of this age-related chronic inflammation is not clear, and may well be due to multiple factors. However, senescent cells are certainly a potential cause or contributor to the chronic inflammation that characterizes aging tissues. It is well-established that chronic inflammation is a major contributor to the development of cancer9,10. Moreover, the growing tumor itself has a profound effect on the tissue microenvironment and can eventually remodel the tissue to support the tumor’s own progression11.
Thus, cancers rise exponentially with age owing to the confluence of two requisite conditions for malignant growth: an accumulation of mutations and age-related changes to tissue microenvironments and even the systemic milieu, both of which can fuel tumor progression.
At advanced ages – for example, more than 80 years of age – overall deaths due to cancer tend to decline. This decline is a bit deceptive, though.
In the cases of some cancers (for example, lung and breast cancer), the incidence of those cancers declines; in addition, the tumor that do form tend to be ‘indolent’ – that is, they are slow-growing and not very aggressive12,13. The reason for the lower prevalence of those advanced-age cancers is not entirely clear. One possibility is that individuals with genetic compositions that make them susceptible to cancer die early -- prior to age 80 or so, such that the surviving individuals have ‘good’ gene combinations that make them more resistant to cancer. Another possibility is that aged tissues or the aged systemic milieu may be less favorable for cancer progression. For example, as noted above, malignant tumors must attract blood supply to provide themselves with needed nutrients (angiogenesis). Old blood vessels, however, are less responsive to angiogenesis signals and less capable of proliferating to form new blood vessels14,15.
There are other cancers, though, that do not decline at advanced ages (for example, colon and bladder cancer)12,13. Rather, they continue to increase in incidence. In addition, the prognosis for certain cancers (for example, certain leukemias and ovarian cancer) worsens with age12,13. These poorer prognoses might be due to the fact that anti-cancer treatments are harder on elderly frail individuals, but they are also due to the biology of these advanced-age cancers, which often make them resistant to standard therapies12,13.
There are still many unanswered questions regarding the relationship between aging and cancer. Answers to these questions will depend critically on more basic research aimed at understanding how aging modifies both the incidence and progression of malignant tumors.
A recent study from the Mayo Clinic suggests that it may eventually be possible to flush out senescent cells from tissue. What do you think the impact of such a procedure on cancer risk would be?
This study16 was an important demonstration that the presence of senescent cells can indeed be deleterious in a living organism (in this case a mouse). The study showed that clearance of senescent cells (using a combined genetic and pharmacological intervention) can improve a number of degenerative tissue changes that occur during aging. In principle, clearing senescent cells should also reduce the risk of cancer because senescent cells are thought to contribute to changes in the tissue microenvironment that support cancer progression.
While the idea of clearing senescent cells holds much promise for reducing the incidence or at least the impact of both degenerative and neoplastic diseases of aging, there will undoubtedly be some complications that may require careful dosing or timing of such an intervention. For example, there is some evidence that senescent cells and the SASP may be beneficial during wound healing17. It would not be wise, then, for example, to clear senescent cells before or shortly after surgery. Nonetheless, developing interventions that eliminate senescent cells or suppress the SASP are an obvious way forward toward mitigating those aspects of age-related tissue degeneration or cancer progression that are fueled by senescent cells.
Are these discoveries and theories about aging cells and cancer changing cancer detection and treatment today?
There is now a robust impetus to more fully understand the benefits and deleterious effects of senescent cells. In concert, there is also a strong impetus to develop pharmacological interventions that can remove senescent cells from the body, or at least dampen their deleterious secretions. It is always difficult to predict when new basic discoveries will lead to concrete intervention in the clinic. However, in the case of senescent (aging) cells, and particularly their impact on cancer, the basic discoveries have not only sparked interest among basic scientists, but they have also sparked interest from representatives of the pharmaceutical industry and clinicians – both oncologists and geriatricians. Thus, I am hopeful that the collaborations that are being formed among these very different experts will soon be manifest in the clinic in the form of new ways to prevent, detect and treat cancer, as well as a host of other age-related diseases.
12/18/2011
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November 2, 2023
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