Today's open access paper reports on a new senolytic drug candidate, with good-looking data on its effects on the bone marrow environment in aged mice - reducing inflammation, and improving the hematopoietic stem cell pool, among other benefits. Senolytic drugs are those that selectively destroy senescent cells. Cells become senescent constantly, but near all either self-destruct or are destroyed by the immune system. Unfortunately, a tiny fraction linger, and their behavior produces chronic inflammation and degrades tissue function in a variety of ways. Their growing presence is one of the root causes of aging, directly implicated in the progression of many age-related diseases. If, however, senescent cells could be periodically culled, safely and efficiently, this contribution to degenerative aging could be removed entirely.
In recent years, researchers have found a dozen or so senolytic compounds. These are largely well-known to the research community, and most have been tested in dozens of studies, usually for anti-cancer effects. Yet next to no-one was looking for effects on cellular senescence much before six or seven years ago, more is the pity. The best of these senolytics have since been demonstrated to clear out between 25% and 50% of senescent cells in some tissues in old mice. A few are proceeding into human studies, the first of which is a pilot conducted by Betterhumans, alongside a fair degree of quiet self-experimentation. Here is a question to consider: given this, just how many more senolytics should we expect to exist in the body of compounds that are already well explored, with good data on side-effects and pharmacokinetics in mice and humans? I think it quite likely that the number is large.
This is a good thing, because we should expect these senolytic pharmaceuticals to be quite varied in their effectiveness by tissue type. The accumulation of evidence is beginning to suggest that senescent cells have their differences, and thus any given mechanism that can tip them over into self-destruction will work well for some tissues, poorly or not at all for others. The best pharmaceutical approach to senescent cells will likely involve a mix of several different classes of compound. This is distinct from the non-pharmaceutical approaches, such as the Oisin Biotechnologies gene therapy or SIWA Therapeutics immunotherapy, that will likely be more broadly effective and reliable, capable of clearly a much higher faction of senescent cells, but at greater expense.
The compound examined here, tetramethylpyrazine, is well studied and widely used in various forms. Take a look at PubMed and you will find a flood of papers from just the past few years, as well as a lengthy period of study over the few decades prior, assessing the benefits of tetramethylpyrazine for a range of age-related conditions. Researchers think it promising for stroke, neurodegeneration, reduction of chronic inflammation, and more. Like a number of the other established compounds that have turned out to be meaningfully senolytic, it is inexpensive and widely available for purchase in the open marketplace. If a compound this well studied can turn out to be senolytic to a significant degree, what else is right underneath the noses of the scientific community, lurking in the sizable batch of promising compounds that are under evaluation at any given time? Equally, if a widely used compound can be senolytic to this degree, that should perhaps temper our expectations on the size of the gains that this approach alone can achieve in humans.
During aging, bone homeostasis is interrupted with the chaos of the marrow microenvironment, including a disrupted hematopoietic stem cell (HSC) niche, decreased vessel formation and abnormal inflammation factor release. As a result, increased cellular senescence in bone marrow can be induced by cellular damage or environment changes. It is reported that senescent cells (SnCs) accumulate in bone marrow with aging and contribute to age-related pathologies through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Although cell senescence has been well studied in recent decades, the mechanisms and local treatment targets for SnCs-induced bone degenerative disease are not well understood.
Mesenchymal stromal cells (MSCs), including mesenchymal stem/progenitor cells (MSPCs), play an essential role in bone metabolism and HSC maintenance. MSC senescence during aging markedly impairs the HSC niche, decreases osteoblast numbers and disrupts epithelial-mesenchymal transition. LepR+ cells in bone marrow were a major source of MSPCs in adult and formed bone, cartilage, and adipocytes in culture and upon transplantation. Additionally, LepR+ cells are essential for maintaining the HSC niche. However, little is known about whether LepR+ cells are senescent and dysfunctional during aging.
Tetramethylpyrazine (TMP), the bioactive component extracted from Ligusticum wallichii Franchat (Chuanxiong) which is widely used for the treatment of ischaemic stroke, cerebral infarction, and degenerative diseases of the central nervous system, has been reported to have anti-inflammatory and anticancer effects in certain cell types. In this study, we aimed to investigate the local effect of TMP on the bone marrow of aging mice and to determine whether the senescent phenotype of MSCs could be eliminated. Our findings revealed that local delivery of TMP eliminates the senescent phenotype of LepR+ MSCs via epigenetically modulating angiogenic environment in aging mice.
Senescent cell (SnC) accumulation in bone marrow with aging leads to aging-related pathologies, and local ablation of SnCs attenuates several pathologic processes and extends a healthy lifespan. In this study, we found that senescent LepR+ MSPCs accumulated in the bone marrow of aging mice with bone degeneration and that local delivery of TMP in bone marrow inhibited LepR+ MSPC senescence. In this study, we just began to understand that local elimination of senescent MSPCs in bone marrow is critical to aging-related bone degenerative change and microenvironment disruption. Identification of the local treatment for cellular senescence and the underlying mechanism of the crosstalk between SnCs and niche cells in maintaining whole bone homeostasis remain interesting for further investigation, which will provide insight into extensive clinical studies in use of local treatment for bone degenerative and regenerative applications.