For the overwhelming majority of patients, type 2 diabetes is a self-inflicted condition. It is the consequence of excess visceral fat tissue, accumulated and held over the years. This type of fat is metabolically active and distorts the operation of metabolism in ways that accelerate the progression of many aspects of aging and age-related disease. Even quite late in the progression of the condition, patients can effectively turn back type 2 diabetes and its consequences via the use of a sustained low calorie diet and consequent weight loss. That more people do not do this is quite eye-opening, given that the alternative is unpleasant medications, side-effects, and the continuation of the disease process leading to an early death.
One of the primary ways in which visceral fat causes harm is via increased levels of chronic inflammation. Inflammation is a necessary part of the immune response to pathogens and injury, provided it lasts a short time only. But when it runs continually, it produces significant dysfunction in tissue maintenance and repair, and accelerates disease processes in all of the common age-related conditions. Visceral fat tissue can produce inflammation in numerous ways: because fat cells secrete signals similar to those of infected cells; fat cells tend to produce DNA debris that can provoke the immune system; and, relevant to research noted here, greater amounts of fat tissue encourage the creation of larger numbers of senescent cells.
The accumulation of lingering senescent cells in all tissues of the body is one of the fundamental causes of aging. Cells become senescent in large numbers constantly, day in and day out, largely resulting from somatic cells reaching the Hayflick limit on replication. Cells can also become senescent as the result of injury, DNA damage, a toxic environment, and the signals of other, nearby senescent cells. Near all senescent cells are quickly destroyed, either self-destructing via apoptosis, or removed by the immune system. It is the tiny fraction that evade this fate that contribute to aging. They largely achieve this end via a potent mix of secreted signals that spur chronic inflammation, destructive remodeling of the surrounding extracellular matrix, and altered behavior in normal cells. Wherever we see chronic inflammation in aging, we should be thinking of senescent cells.
Fortunately, senolytic therapies to selectively destroy senescent cells are presently under active development. New biotechnology companies and development programs are arriving in this part of the industry on a regular basis now, and a significant and growing amount of funding is now available for this work. Even better, a range of low-cost, easily obtained drugs and other compounds (such as the dasatinib and quercetin combination, fisetin, piperlongumine, and the FOXO4-DRI peptide) have been shown to remove a fair fraction of senescent cells in animal studies. Some are presently in initial human trials. Any older person suffering one or more of the many age-related conditions that appear likely to be actively maintained and driven by senescent cells, and who wishes to responsibly self-experiment with senolytics, can certainly do so with just a little knowledge and effort. These are interesting times.
Inflammation and dysfunction of fat tissue cause some of the insulin resistance in obese people. In many cases, that dysfunction is caused by senescent cells that already have been shown to be responsible for conditions related to aging and illness, including osteoporosis, muscle weakness, nerve degeneration, and heart disease. These cells also accumulate in the fat tissues of obese and diabetic people and mice.
In this study, the researchers, using genetically modified mice and wild-type (normal) mice, removed senescent cells two ways: by causing genetically-mediated cell death and by administering a combination of senolytic drugs. Senolytic drugs selectively kill senescent cells but not normal cells. The result: glucose levels and insulin sensitivity improved. The mice also showed a decline in inflammatory factors and a return to normal fat cell function. The senolytic drugs also prompted improved kidney and heart function, both of which are common complications of diabetes.
Cellular senescence is a cell fate that entails proliferative arrest and acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP). Although senescent cells exist in relatively small numbers in any particular tissue, they have been associated with multiple diseases of aging and are emerging as useful therapeutic targets for age-related diseases, including cardiovascular disease, pulmonary fibrosis, neurodegeneration, and osteoporosis. A number of stimuli, including potentially oncogenic, inflammatory, damage-related, and metabolic stimuli, can trigger a senescence response. Components of the SASP secreted by adipose-derived senescent cells have been postulated to confer insulin resistance upon metabolic tissues, inhibit adipogenesis, and attract immune cells that can exacerbate insulin resistance. Here, we determined whether removing senescent cells in the context of obesity improves metabolic phenotypes.
Recently, drugs that preferentially decrease senescent cell burden, termed senolytics, have been identified. We discovered the first senolytics based on our observation that senescent cells rely on several survival pathways to confer resistance to their pro-apoptotic SASP and intracellular cell damage signals. Knowing this, we identified dasatinib (D) and quercetin (Q) as orally bioactive drugs that transiently target these survival pathways to induce apoptosis preferentially in senescent cells.
We employed the combination of D plus Q (D + Q) in our studies for the following reasons. (a) In our hands, no senolytic investigated thus far targets all types of senescent cells. For example, unlike navitoclax (ABT263), fisetin, A1331852, A1155463, or Q on its own, D selectively targets senescent adipose progenitors, a key cell type for adipose tissue and metabolic function. (b) On the other hand, Q, unlike D, is effective against senescent endothelial cells, a cell type implicated in vascular complications of diabetes. (c) D + Q is effective in alleviating multiple age- and senescence-associated disorders, including many that are frequent complications or comorbidities of diabetes in preclinical animal models.
Here, we show that reducing senescent cell burden in obese mice, either by activating drug-inducible "suicide" genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra-abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity-related metabolic dysfunction and its complications.